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Abba Moussa D, Vazquez M, Chable-Bessia C, Roux-Portalez V, Tamagnini E, Pedotti M, Simonelli L, Ngo G, Souchard M, Lyonnais S, Chentouf M, Gros N, Marsile-Medun S, Dinter H, Pugnière M, Martineau P, Varani L, Juan M, Calderon H, Naranjo-Gomez M, Pelegrin M. Discovery of a pan anti-SARS-CoV-2 monoclonal antibody with highly efficient infected cell killing capacity for novel immunotherapeutic approaches. Emerg Microbes Infect 2025; 14:2432345. [PMID: 39584380 PMCID: PMC11632933 DOI: 10.1080/22221751.2024.2432345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 10/24/2024] [Accepted: 11/17/2024] [Indexed: 11/26/2024]
Abstract
Unlocking the potential of broadly reactive coronavirus monoclonal antibodies (mAbs) and their derivatives offers a transformative therapeutic avenue against severe COVID-19, especially crucial for safeguarding high-risk populations. Novel mAb-based immunotherapies may help address the reduced efficacy of current vaccines and neutralizing mAbs caused by the emergence of variants of concern (VOCs). Using phage display technology, we discovered a pan-SARS-CoV-2 mAb (C10) that targets a conserved region within the receptor-binding domain (RBD) of the virus. Noteworthy, C10 demonstrates exceptional efficacy in recognizing all assessed VOCs, including recent Omicron variants. While C10 lacks direct neutralization capacity, it efficiently binds to infected lung epithelial cells and induces their lysis via natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Building upon this pan-SARS-CoV-2 mAb, we engineered C10-based, Chimeric Antigen Receptor (CAR)-T cells endowed with efficient killing capacity against SARS-CoV-2-infected lung epithelial cells. Notably, NK and CAR-T-cell mediated killing of lung infected cells effectively reduces viral titers. These findings highlight the potential of non-neutralizing mAbs in providing immune protection against emerging infectious diseases. Our work reveals a pan-SARS-CoV-2 mAb effective in targeting infected cells and demonstrates the proof-of-concept for the potential application of CAR-T cell therapy in combating SARS-CoV-2 infections. Furthermore, it holds promise for the development of innovative antibody-based and cell-based therapeutic strategies against severe COVID-19 by expanding the array of therapeutic options available for high-risk populations.Trial registration: ClinicalTrials.gov identifier: NCT04093596.
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Affiliation(s)
| | - Mario Vazquez
- IDIBAPS, Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses, Barcelona, Spain
- Department of Immunology, Hospital Clínic de Barcelona, Barcelona, Spain
| | | | - Vincent Roux-Portalez
- IRCM, University of Montpellier, ICM, INSERM, Montpellier, France
- GenAc, Siric Plateform, INSERM, Montpellier, France
| | - Elia Tamagnini
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
| | - Mattia Pedotti
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
| | - Luca Simonelli
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
| | - Giang Ngo
- IRCM, University of Montpellier, ICM, INSERM, Montpellier, France
- PPM, BioCampus Plateforme de Protéomique de Montpellier CNRS, Montpellier, France
| | - Manon Souchard
- IRMB, University of Montpellier, INSERM, CNRS, Montpellier, France
| | | | - Myriam Chentouf
- IRCM, University of Montpellier, ICM, INSERM, Montpellier, France
- GenAc, Siric Plateform, INSERM, Montpellier, France
| | - Nathalie Gros
- CEMIPAI, University of Montpellier, UAR3725 CNRS, Montpellier, France
| | | | - Heiko Dinter
- IRMB, University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Martine Pugnière
- IRCM, University of Montpellier, ICM, INSERM, Montpellier, France
- PPM, BioCampus Plateforme de Protéomique de Montpellier CNRS, Montpellier, France
| | - Pierre Martineau
- IRCM, University of Montpellier, ICM, INSERM, Montpellier, France
- GenAc, Siric Plateform, INSERM, Montpellier, France
| | - Luca Varani
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
| | - Manel Juan
- IDIBAPS, Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses, Barcelona, Spain
- Department of Immunology, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Hugo Calderon
- IDIBAPS, Immunogenetics and Immunotherapy in Autoinflammatory and Immune Responses, Barcelona, Spain
- Department of Immunology, Hospital Clínic de Barcelona, Barcelona, Spain
| | | | - Mireia Pelegrin
- IRMB, University of Montpellier, INSERM, CNRS, Montpellier, France
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de Groot BO, Biserni C, Fuermaier ABM, Enriquez-Geppert S. Untreated if unrecognized: A cognitive profile of sustained subjective executive dysfunctions in COVID-19. APPLIED NEUROPSYCHOLOGY. ADULT 2025; 32:903-913. [PMID: 37334922 DOI: 10.1080/23279095.2023.2223329] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2023]
Abstract
& STATEMENT OF IMPACTSARS-COV-2 infection can result in acute and long-lasting cognitive complaints, causing ongoing impairments in daily life which poses a challenge to society. Consequently, the evaluation and characterization of cognitive complaints, specifically in the domain of executive functions (EFs) affecting daily life, is imperative in formulating an effective neuropsychological response.In total 442 participants aged 18-65+ years from the Netherlands, Germany, Mexico, and Spain were included in an online questionnaire. Among others, the questionnaire consisted of demographics, the Behavior Rating Inventory of Executive Functioning for Adults (BRIEF-A), measures of subjective disease progression severity and experienced subjective impairment in daily activities. To assess whether daily life activities are affected by EF impairments, the main BRIEF-A composite score (GEC) was analyzed. To determine whether disease-related COVID-19 factors predict EFs complaints in daily life, a stepwise regression analysis was performed with i) experienced disease severity, ii) time since disease, and iii) health risk factor as predictors.The study revealed noteworthy differences in the occurrence of EFs problems in daily life between both groups, as indicated by the GEC, which exhibited a medium effect size even 6 months post-COVID-19 diagnosis even in mild disease progression. The scores of the BRIEF-A subscales follow a domain-specific profile, and includes clinically relevant impairments in: Working memory, Plan/Organize, Task Monitor, Shift, which are affected by the experienced severity of the disease. This cognitive profile has important implications for targeted cognitive training in rehabilitation and has the potential for an applicability to other viruses as well.
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Affiliation(s)
- Bob O de Groot
- Department of Clinical and Developmental Neuropsychology, University of Groningen, The Netherlands
| | - Chiara Biserni
- Department of Clinical and Developmental Neuropsychology, University of Groningen, The Netherlands
| | - Anselm B M Fuermaier
- Department of Clinical and Developmental Neuropsychology, University of Groningen, The Netherlands
| | - Stefanie Enriquez-Geppert
- Department of Clinical and Developmental Neuropsychology, University of Groningen, The Netherlands
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, Groningen, The Netherlands
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3
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Xiao W, Zhang L, Zhang Y, Hu J, Zhang J, Hua T, Yang M. Association between serum ferritin and mortality in patients with severe fever with thrombocytopenia syndrome: A retrospective cohort study. PLoS Negl Trop Dis 2025; 19:e0013104. [PMID: 40402996 DOI: 10.1371/journal.pntd.0013104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 05/04/2025] [Indexed: 05/24/2025] Open
Abstract
The role of serum ferritin, an acute-phase inflammatory marker, in predicting mortality in patients with severe fever with thrombocytopenia syndrome (SFTS) is not fully understood. This study aimed to investigate the association between serum ferritin levels and inpatient mortality in patients with SFTS. We conducted a retrospective analysis using data from patients diagnosed with SFTS at the Second Affiliated Hospital of Anhui Medical University between May 2017 and September 2024. The association between serum ferritin levels and in-hospital mortality in patients with SFTS was assessed using Cox regression models and restricted cubic spline (RCS) analysis. The receiver operating characteristic (ROC) curve was used to determine the optimal serum ferritin cut-off value for predicting mortality risk. Kaplan-Meier survival curves were compared for survival rates, and propensity score matching with linear trend testing was applied to ensure robustness. This study included 390 patients with SFTS, of whom 312 survived and 78 did not, yielding an in-hospital mortality rate of 20.0%. Cox regression and RCS analyses demonstrated a significant linear association between higher serum ferritin levels and increased in-hospital mortality in patients with SFTS, indicating that the predicted mortality of patients with SFTS increased with elevated serum ferritin levels beyond a certain threshold. ROC analysis revealed an area under the curve of 0.830, with an optimal serum ferritin cut-off of 3.975 (lg, ng/ml), sensitivity of 0.731, and specificity of 0.830. Clinically, serum ferritin levels above 4 (lg ng/ml), were associated with a substantial increase in mortality risk. Sensitivity analysis supported the robustness of these results. Serum ferritin levels are linearly associated with mortality risk in patients with SFTS, with mortality significantly increasing when serum ferritin levels exceed 10,000 ng/ml. Serum ferritin level may serve as a valuable prognostic biomarker for mortality risk in patients with SFTS.
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Affiliation(s)
- Wenyan Xiao
- The Second Department of Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
- The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
| | - Liangliang Zhang
- The Second Department of Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
- The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
| | - Yang Zhang
- The Second Department of Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
- The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
| | - Juanjuan Hu
- The Second Department of Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
- The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
| | - Jin Zhang
- The Second Department of Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
- The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
| | - Tianfeng Hua
- The Second Department of Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
- The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
| | - Min Yang
- The Second Department of Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
- The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, P.R.China
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Hsieh LL, Thompson EA, Jairam NP, Roznik K, Figueroa A, Aytenfisu T, Zhou W, Gour N, Chao KH, Milstone AM, Egbert E, D'Alessio F, Karakousis PC, Ordoñez A, Scully EP, Pekosz A, Karaba AH, Cox AL. SARS-CoV-2 induces neutrophil degranulation and differentiation into myeloid-derived suppressor cells associated with severe COVID-19. Sci Transl Med 2025; 17:eadn7527. [PMID: 40397714 DOI: 10.1126/scitranslmed.adn7527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 11/18/2024] [Accepted: 04/01/2025] [Indexed: 05/23/2025]
Abstract
Severe COVID-19 presents with a distinct immunological profile, characterized by elevated neutrophil and reduced lymphocyte counts, seen commonly in fungal and bacterial infections. This study demonstrates that patients hospitalized with COVID-19 show evidence of neutrophil degranulation and have increased expression of neutrophil surface lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a marker of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Both early LOX-1 and programmed death-ligand 1 (PD-L1) expression on neutrophils were associated with development of severe disease. To determine whether tissue damage or inflammation is required to induce PMN-MDSCs or whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly activates neutrophils to become PMN-MDSCs, we incubated healthy human neutrophils with SARS-CoV-2. SARS-CoV-2 rapidly induced LOX-1 surface expression in healthy neutrophils independent of productive infection. LOX-1 induction was dependent on granule exocytosis and promoted up-regulation of reactive oxygen species, CD63, and PD-L1, enabling LOX-1+ neutrophils to suppress autologous T cell proliferation in vitro. These results support a role for PMN-MDSCs in mediating severe COVID-19, and inhibition of PD-L1 represents a potential therapeutic strategy for enhancing the immune response in acute SARS-CoV-2 infection.
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Affiliation(s)
- Leon L Hsieh
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Elizabeth A Thompson
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Nirvani P Jairam
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Katerina Roznik
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Alexis Figueroa
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Tihitina Aytenfisu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Weiqiang Zhou
- Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Naina Gour
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Kuan-Hao Chao
- Center for Computational Biology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Aaron M Milstone
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Emily Egbert
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Franco D'Alessio
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Petros C Karakousis
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Alvaro Ordoñez
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Eileen P Scully
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Andrew Pekosz
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Andrew H Karaba
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Andrea L Cox
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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5
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Duan Y, Ou Y, Li J, Gan X, Cao J. Serum cytokine levels in children with community-acquired pneumonia caused by different respiratory pathogens. Ital J Pediatr 2025; 51:147. [PMID: 40394688 PMCID: PMC12093880 DOI: 10.1186/s13052-025-02012-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 05/11/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Our study aims to investigate the levels of serum cytokines in children with community-acquired pneumonia (CAP) caused by different respiratory pathogens, and evaluate the predictive value of cytokines levels for severe pneumonia. METHODS A retrospective study was conducted on the clinical data of children hospitalized with CAP. According to the pathogens, patients were divided into the M. pneumoniae group, Adenovirus group, respiratory syncytial virus group, H.influenzae group, and S.pneumoniae group. RESULTS The M. pneumoniae group was higher than RSV group in the level of serum pro-inflammatory cytokines include IL-2, IL-6, IL-17 A, and IFN-γ. But M. pneumoniae group was higher than Adenovirus group only in IL-6. M. pneumoniae group was higher than H. influenzae group and S. pneumoniae group in IL-17 A, IFN-γ. as primary anti-inflammatory cytokine, IL-10 was lower in the M. pneumoniae group compared with Adenovirus and RSV groups. IL-6 was higher in S. pneumoniae group than RSV group. IFN-γ was lower in H. influenzae group than Adenovirus group and RSV group. IL-10 was higher in RSV group than H. influenzae group. IL-6 was higher in Adenovirus group than RSV group. In M. pneumoniae group and H. influenzae group, the levels of IL-6, IL-10, and IFN-γ were significantly higher in the severe pneumonia subgroup compared with the non-severe pneumonia subgroup (P < 0.05). CONCLUSIONS Compared with other groups, M. pneumoniae group was higher in the level of serum proinflammatory cytokines. Additionally, the levels of IL-6, IL-10, and IFN-γ can be used as predictors of severe pneumonia caused by M. pneumoniae and H. influenzae.
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Affiliation(s)
- Yuanhui Duan
- Department of Medical General Ward Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Yuexu Ou
- Department of Medical General Ward Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Jieling Li
- Department of Medical General Ward Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Xiaoming Gan
- Department of Medical General Ward Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Jie Cao
- Department of Medical General Ward Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China.
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6
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Davis-Porada J, Tozlu C, Aiello C, Apostolidis SA, Bar-Or A, Bove R, Espinoza DA, Ferreira Brito S, Jacobs D, Kakara M, Onomichi K, Ricci A, Sabatino JJ, Walker E, Wherry EJ, Zhang L, Zhu W, Xia Z, De Jager P, Wesley SF, Straus Farber R, Farber DL. Durable T cell immunity to COVID-19 vaccines in MS patients on B cell depletion therapy. NPJ Vaccines 2025; 10:98. [PMID: 40382362 PMCID: PMC12085558 DOI: 10.1038/s41541-025-01151-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 04/30/2025] [Indexed: 05/20/2025] Open
Abstract
Immune-mediated protection generated to COVID-19 mRNA vaccines is associated with anti-Spike (S) protein neutralizing antibodies. However, humoral immunity is compromised in B cell depleting (BCD) therapies, used to treat autoimmune diseases such as Multiple Sclerosis (MS). To study the effect of BCD on the durability and protective efficacy of vaccine-induced immunity, we evaluated S-reactive antibodies and T cell responses 1-70 weeks post-vaccination in MS cohorts treated with BCD compared to non-BCD therapies from four centers. BCD-treated participants had significantly reduced antibody levels and enhanced frequencies of S-reactive CD4+ and CD8+ memory T cells to COVID-19 vaccination compared to the non-BCD group, with some variations among different BCD formulations. T cell memory responses persisted up to 14 months post-vaccination in both BCD and non-BCD cohorts, who experienced similar clinical protection from COVID-19. Together, our results establish a critical role for T cell-mediated immunity in anti-viral protection independent of humoral immunity.
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Affiliation(s)
- Julia Davis-Porada
- Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA
- Medical Scientist Training Program, Columbia University Irving Medical Center, New York, NY, USA
| | - Ceren Tozlu
- Department of Radiology, Weill Cornell Medicine, New York, NY, USA
| | - Claudia Aiello
- Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA
- Medical Scientist Training Program, Columbia University Irving Medical Center, New York, NY, USA
| | - Sokratis A Apostolidis
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Division of Rheumatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Amit Bar-Or
- Center for Neuroinflammation and Experimental Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Riley Bove
- UCSF Weill Institute for Neuroscience, Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Diego A Espinoza
- Center for Neuroinflammation and Experimental Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Immunology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Sugeidy Ferreira Brito
- Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, Neurology, Columbia Multiple Sclerosis Center and Center for Translational & Computational Neuroimmunology, New York, NY, USA
| | - Dina Jacobs
- Center for Neuroinflammation and Experimental Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Mihir Kakara
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
| | - Kaho Onomichi
- Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, Neurology, Columbia Multiple Sclerosis Center and Center for Translational & Computational Neuroimmunology, New York, NY, USA
| | - Adelle Ricci
- Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, Neurology, Columbia Multiple Sclerosis Center and Center for Translational & Computational Neuroimmunology, New York, NY, USA
| | - Joseph J Sabatino
- UCSF Weill Institute for Neuroscience, Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Elizabeth Walker
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - E John Wherry
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Lili Zhang
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Wen Zhu
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Zongqi Xia
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Philip De Jager
- Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, Neurology, Columbia Multiple Sclerosis Center and Center for Translational & Computational Neuroimmunology, New York, NY, USA
| | - Sarah Flanagan Wesley
- Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, Neurology, Columbia Multiple Sclerosis Center and Center for Translational & Computational Neuroimmunology, New York, NY, USA.
| | - Rebecca Straus Farber
- Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, Neurology, Columbia Multiple Sclerosis Center and Center for Translational & Computational Neuroimmunology, New York, NY, USA.
| | - Donna L Farber
- Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA.
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7
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Gong Z, An H. Integrated transcriptomic analysis of COVID-19 stages and recovery: insights into key gene signatures, immune features, and diagnostic biomarkers through machine learning. Front Genet 2025; 16:1599867. [PMID: 40444276 PMCID: PMC12119500 DOI: 10.3389/fgene.2025.1599867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Accepted: 05/06/2025] [Indexed: 06/02/2025] Open
Abstract
Background COVID-19 progression and recovery involve complex gene expression changes and immune dysregulation, but their dynamic alterations remain poorly understood. Current clinical indicators lack precision in distinguishing severe cases, highlighting the need for molecular biomarkers and diagnostic tools. Methods Three transcriptomic datasets were analyzed: 1) COVID-19 progression from Healthy, Moderate, Severe, to ICU patients; 2) recovery stages (1, 3, and 6 months) compared to Healthy controls; and 3) COVID-19 ICU versus non-ICU patients. Differential expression analysis, immune cell infiltration estimation, machine learning (LASSO regression and random forest), and functional enrichment were used to identify key genes and molecular mechanisms. Results Gene expression analysis revealed dynamic changes during COVID-19 progression. Adaptive immune cells (e.g., B cells and T cells) decreased, while innate immune cells (e.g., monocytes and neutrophils) increased, particularly in ICU patients. Recovery analysis showed significantly reduced adaptive immune cells at 1 month, with partial recovery by 3 and 6 months. Machine learning identified CCR5, CYSLTR1, and KLRG1 as diagnostic biomarkers for distinguishing ICU from non-ICU patients, with AUC values of 0.916, 0.885, and 0.899, respectively. Conclusion This study identified CCR5, CYSLTR1, and KLRG1 as efficient diagnostic biomarkers for severe COVID-19 using machine learning and revealed immune regulatory features across COVID-19 progression and recovery.
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Affiliation(s)
- Zhiyuan Gong
- School of Medical Technology, Tianjin Medical University, Tianjin, China
| | - He An
- Department of Clinical Laboratory, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
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8
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Liu QD, Wang DX. Association between Prognostic Nutritional Index and Mortality Risk in Critically Ill Patients with Chronic Obstructive Pulmonary Disease: A Retrospective Study. Int J Chron Obstruct Pulmon Dis 2025; 20:1493-1508. [PMID: 40395875 PMCID: PMC12089260 DOI: 10.2147/copd.s517676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Accepted: 05/01/2025] [Indexed: 05/22/2025] Open
Abstract
Background The Prognostic Nutritional Index (PNI), an integrative measure of body's immune and nutritional status, has demonstrated its prognostic value across a range of diseases. However, its role in critically ill patients with Chronic Obstructive Pulmonary Disease (COPD) remains unclear. This study investigates the association between PNI levels and clinical outcomes in critically ill COPD patients, with a focus on identifying its role as a potential predictor of mortality. Methods A retrospective analysis of 1,250 critically ill COPD patients from the MIMIC-IV (v2.2) database was conducted. Patients were grouped by PNI tertiles. Primary and secondary outcomes were 28-day and 90-day mortality, respectively. Associations were evaluated using restricted cubic splines, Cox proportional hazards regression analysis, and Kaplan‒Meier survival curves. The predictive performance of PNI was assessed via receiver operating characteristic (ROC) curves analysis, and a nomogram integrating Boruta-selected features was developed to enhance clinical utility. Results The final cohort comprised 1,250 critically ill COPD patients, with observed mortality rates of 25.3% and 33.2% at 28 and 90 days, respectively. Higher PNI levels were associated with reduced risk of both 28-day and 90-day mortality [28-day HR: 0.95 (95% CI: 0.93-0.97), P < 0.001; 90-day HR: 0.94 (95% CI: 0.93-0.96), P < 0.001]. Restricted cubic spline analysis confirmed this trend. Furthermore, ROC analysis demonstrated the utility of PNI as a predictor for 28-day mortality (AUC: 0.61). Boruta-selected features reinforced the importance of PNI, and the constructed nomogram exhibited excellent predictive accuracy (AUC: 0.712). Conclusion Higher PNI is linked to reduced mortality risk in critically ill COPD patients, indicating its potential as a prognostic marker.
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Affiliation(s)
- Qiu-Die Liu
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Dao-Xin Wang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
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9
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Cheng X, Liu L, Tian Y, Lin Y. Serum lactate dehydrogenase as a prognostic marker for 90-day mortality in connective tissue disease patients receiving glucocorticoids and hospitalized with pneumonia: a cohort study. Sci Rep 2025; 15:16806. [PMID: 40369099 PMCID: PMC12078684 DOI: 10.1038/s41598-025-01721-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 05/07/2025] [Indexed: 05/16/2025] Open
Abstract
Elevated serum lactate dehydrogenase (LDH) levels have been associated with poor prognosis in various diseases. This study investigates the relationship between serum LDH levels and 90-day mortality in patients with connective tissue disease (CTD) receiving glucocorticoids and hospitalized with pneumonia. A total of 298 CTD patients were included in this study. The cohort was divided into three groups based on serum LDH levels (Group 1: < 246 U/L, 0% mortality; Group 2: 246-407 U/L, 26% mortality; Group 3: ≥ 407 U/L, 48% mortality). Clinical and laboratory data were analyzed to evaluate the association between LDH levels and 90-day mortality using Kaplan-Meier survival curves, Cox regression models, and subgroup analyses. Elevated LDH levels were significantly associated with increased mortality. The Kaplan-Meier survival analysis demonstrated that patients in Group 3 (highest LDH levels) had the highest 90-day mortality rate, while those in Group 1 (lowest LDH levels) had the lowest (p < 0.0001). Multivariate Cox regression analysis revealed that every 100 U/L increase in LDH was associated with a higher risk of mortality (HR 1.07, 95% CI 1.01-1.13, p = 0.02). Patients in Group 3 showed a significantly increased risk of mortality (HR 2.29, 95% CI 1.06-4.96, p = 0.036). The subgroup analyses demonstrated stable results across different clinical subgroups. Elevated serum LDH levels, particularly in Group 3, are independently associated with increased 90-day mortality in CTD patients receiving glucocorticoids and hospitalized with pneumonia. LDH may serve as an important prognostic marker for these patients.
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Affiliation(s)
- Xiangkuan Cheng
- Department Care Unit, Hebei Yanda Lu Daopei Hospital, Langfang, 065201, Hebei Province, China
| | - Lanling Liu
- Department of Respiratory and Critical Care Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China
| | - Yueming Tian
- Department Care Unit, Hebei Yanda Lu Daopei Hospital, Langfang, 065201, Hebei Province, China
| | - Yuansheng Lin
- Department of Intensive Care Unit, Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 1 Lijiang Road, Suzhou, 215000, China.
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10
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Khandelwal Y, Ora M, Jain B, Dixit M, Singh P, Khan A, Nath A, Agarwal V, Gambhir S. Post-COVID-19 lung disease: utility of biochemical and imaging markers in uncovering residual lung inflammation and monitoring anti-inflammatory therapy, a prospective study. Eur J Nucl Med Mol Imaging 2025:10.1007/s00259-025-07297-w. [PMID: 40355745 DOI: 10.1007/s00259-025-07297-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 04/21/2025] [Indexed: 05/14/2025]
Abstract
PURPOSE Post-COVID-19 lung disease (PCLD) is a significant concern following the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. PCLD encompasses persistent debilitating respiratory symptoms and radiological changes beyond the acute disease phase. It highlights the ongoing search to identify and manage lingering diseases. This prospective study utilizes F18-Fludeoxyglucose (FDG) PET/CT to identify residual inflammatory lung lesions in PCLD. Treatment response was assessed after anti-inflammatory and antifibrotic therapies. MATERIALS AND METHODS Thirty patients post-severe COVID-19 pneumonia enrolled. They underwent baseline 18F-FDG PET/CT scans to unveil residual lung inflammation lesions on FDG and CT. They received antifibrotic (Pirfenidone) and anti-inflammatory (Methylprednisolone) drugs for 6-12 weeks. They were followed up for clinical, biochemical, and imaging treatment responses. RESULTS Baseline 18F-FDG PET/CT revealed ongoing lung inflammation in all PCLD (mean SUVmax: 3.8 ± 2.3 and number of segments: 8±3 ). The mean CT severity score was 17.7 ± 3.4 with moderate (n = 16) or severe (n = 14) disease involvement. Mild, moderate, and severe 18F-FDG PET/CT categories were noted in the 8, 14, and 8 patients, respectively. Following treatment, a PET scan showed a significant decrease in disease extent (segments) and severity (FDG uptake) and an improvement in disease grading on imaging (97% of patients). In PET concordance, there was a significant clinical and radiological improvement with a fall in inflammatory markers (p < 0.005). Serum Ferritin and total leukocyte counts were significantly associated with PCLD severity on 18F-FDG PET/CT(p < 0.05). CONCLUSION This prospective study identifies and quantifies ongoing significant residual lung inflammation in PCLD on 18F-FDG PET/CT. Anti-inflammatory and antifibrotic drug therapy led to clinical and radiological improvement. 18F-FDG PET/CT as a non-invasive biomarker helped manage and follow up PCLD patients. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
| | - Manish Ora
- Department of Nuclear Medicine, SGPGI, Lucknow, India
| | - Bela Jain
- Department of Nuclear Medicine, AIIMS, New Delhi, India
| | - Manish Dixit
- Department of Nuclear Medicine, SGPGI, Lucknow, India
| | - Prakash Singh
- Department of Nuclear Medicine, KGMC, Lucknow, India
| | - Ajmal Khan
- Department of Pulmonary Medicine, SGPGI, Lucknow, India
| | - Alok Nath
- Department of Pulmonary Medicine, SGPGI, Lucknow, India
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11
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Liu S, Xu W, Tu B, Xiao Z, Li X, Huang L, Yuan X, Zhou J, Yang X, Yang J, Chang D, Chen W, Wang FS. Early Immunological and Inflammation Proteomic Changes in Elderly COVID-19 Patients Predict Severe Disease Progression. Biomedicines 2025; 13:1162. [PMID: 40426989 PMCID: PMC12108611 DOI: 10.3390/biomedicines13051162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/28/2025] [Accepted: 05/01/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Elderly patients infected with SARS-CoV-2 are at higher risk of developing cytokine storm and severe outcomes; however, specific immunological and proteomic biomarkers for early prediction remain unclear in this vulnerable group. Methods: We enrolled 182 elderly COVID-19 patients from the Chinese PLA General Hospital between November 2022 and April 2023, categorizing them based on progression to respiratory failure requiring mechanical ventilation (defined as severe progression). Olink proteomic analysis was performed on admission serum from 40 propensity score-matched samples, with differentially expressed proteins (DEPs) validated by cytometric bead array (CBA) in 178 patients. To predict severe progression, a model was developed using a 70% training set and validated on a 30% validation set. LASSO regression screened features followed by logistic regression and receiver operating characteristic (ROC) analysis to optimize the model by incrementally incorporating features ranked by random forest importance. Results: Elderly patients progressing to severe COVID-19 exhibited early immune dysregulation, including neutrophilia, lymphopenia, monocytopenia, elevated procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6), neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII), as well as coagulation dysfunction and multi-organ injury. Proteomics identified a set of biomarkers, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and revealed disruptions in signaling pathways, including the mTOR and VEGF signaling pathways. The optimal predictive model, which incorporated PCT, IL-6, monocyte percentage, lymphocyte count, and TRAIL, achieved an area under curve (AUC) of 0.870 (0.729-1.000) during validation. TRAIL levels negatively correlated with fibrinogen (p < 0.05). Conclusions: Elderly COVID-19 patients with severe progression demonstrate early immune dysregulation, hyperinflammation, coagulation dysfunction, and multi-organ injury. The model we proposed effectively predicts disease progression in elderly COVID-19 patients, providing potential biomarkers for early clinical risk stratification in this vulnerable population.
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Affiliation(s)
- Shiyang Liu
- Medical School of Chinese PLA, Beijing 100853, China;
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100073, China; (W.X.); (B.T.); (X.L.); (L.H.); (X.Y.); (J.Z.); (X.Y.); (J.Y.)
| | - Wen Xu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100073, China; (W.X.); (B.T.); (X.L.); (L.H.); (X.Y.); (J.Z.); (X.Y.); (J.Y.)
| | - Bo Tu
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100073, China; (W.X.); (B.T.); (X.L.); (L.H.); (X.Y.); (J.Z.); (X.Y.); (J.Y.)
| | - Zhiqing Xiao
- Department of Pulmonary and Critical Care Medicine at The Seventh Medical Center, College of Pulmonary and Critical Care Medicine of The Eighth Medical Center, Chinese PLA General Hospital, Beijing 100007, China; (Z.X.); (D.C.)
| | - Xue Li
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100073, China; (W.X.); (B.T.); (X.L.); (L.H.); (X.Y.); (J.Z.); (X.Y.); (J.Y.)
- Yu-Yue Pathology Scientific Research Center, Chongqing 401329, China
| | - Lei Huang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100073, China; (W.X.); (B.T.); (X.L.); (L.H.); (X.Y.); (J.Z.); (X.Y.); (J.Y.)
| | - Xin Yuan
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100073, China; (W.X.); (B.T.); (X.L.); (L.H.); (X.Y.); (J.Z.); (X.Y.); (J.Y.)
| | - Juanjuan Zhou
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100073, China; (W.X.); (B.T.); (X.L.); (L.H.); (X.Y.); (J.Z.); (X.Y.); (J.Y.)
| | - Xinxin Yang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100073, China; (W.X.); (B.T.); (X.L.); (L.H.); (X.Y.); (J.Z.); (X.Y.); (J.Y.)
| | - Junlian Yang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100073, China; (W.X.); (B.T.); (X.L.); (L.H.); (X.Y.); (J.Z.); (X.Y.); (J.Y.)
| | - De Chang
- Department of Pulmonary and Critical Care Medicine at The Seventh Medical Center, College of Pulmonary and Critical Care Medicine of The Eighth Medical Center, Chinese PLA General Hospital, Beijing 100007, China; (Z.X.); (D.C.)
| | - Weiwei Chen
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100073, China; (W.X.); (B.T.); (X.L.); (L.H.); (X.Y.); (J.Z.); (X.Y.); (J.Y.)
| | - Fu-Sheng Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100073, China; (W.X.); (B.T.); (X.L.); (L.H.); (X.Y.); (J.Z.); (X.Y.); (J.Y.)
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12
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Kakh M, Doroudchi M, Talepoor A. Induction of Regulatory T Cells After Virus Infection and Vaccination. Immunology 2025. [PMID: 40329764 DOI: 10.1111/imm.13927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 03/04/2025] [Accepted: 03/17/2025] [Indexed: 05/08/2025] Open
Abstract
Vaccines have been proven to be one of the safest and most effective ways to prevent and combat diseases. However, the main focus has been on the evaluation of the potency of effector mechanisms and the lack of adverse effects of vaccine candidates. Recently, the importance of induced regulatory mechanisms of the immune system after vaccination has come to light. With the increase in our knowledge about these regulatory mechanisms including the regulatory T cells (Tregs), we have come to understand the significance of this arm of the immune system in controlling immunopathology and/or diminishing the effectiveness of vaccines, especially viral vaccines. Tregs play a dual role during infectious diseases by limiting immune-mediated pathology and also contributing to chronic pathogen persistence by decreasing effector immunity and clearance of infection. Tregs may also affect immune responses after vaccination primarily by inhibiting antigen presenting cell function such as cytokine secretion and co-stimulatory molecule expression as well as effector T (Teff) and B cell function. In this article, we review the current knowledge on the induction of Tregs after several life-threatening virus infections and their available vaccines to bring them to the spotlight and emphasise that studying viral-induced antigen-specific Tregs will help us improve the effectiveness and decrease the immunopathology or side effects of viral vaccines. Trial Registration: ClinicalTrials.gov identifier: NCT04357444.
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Affiliation(s)
- MansourehKarimi Kakh
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehrnoosh Doroudchi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - AtefeGhamar Talepoor
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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13
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Vanderkamp SG, Niazy M, Stegelmeier AA, Stinson KJ, Ricker N, Bridle BW. Cytokine, chemokine, and acute-phase protein profiles in plasma as correlative biomarkers of clinical outcomes for patients with COVID-19. Sci Rep 2025; 15:15397. [PMID: 40316702 PMCID: PMC12048561 DOI: 10.1038/s41598-025-99248-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 04/17/2025] [Indexed: 05/04/2025] Open
Abstract
Coronavirus disease identified in 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2, had a global impact on human health and the economy. The aim of this study was to quantify cytokines, chemokines, and acute phase proteins in the plasma of patients with COVID-19 to elucidate potential biomarkers to inform prognostic and treatment decisions. Clustering analysis using the K-prototypes method identified underlying biological patterns in patients with COVID-19. The penalized multinomial logistic regression analysis identified two comorbidities (hypertension, congestive heart failure) and thirteen analytes as potential risk factors for COVID-19 progression with 88.2% accuracy. Based on a patient's age, high concentrations of interleukin (IL)-6, monocyte chemoattractant protein-1, and pentraxin 3 were important biomarkers for lethal COVID-19. Decreased concentrations of interferon gamma-induced protein-10, IL-10, and soluble tumor necrosis factor receptor I were found to be associated with mild COVID-19, while increasing concentrations of these analytes could be used to predict COVID-19 severity.
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Affiliation(s)
- Sierra G Vanderkamp
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Maysa Niazy
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Ashley A Stegelmeier
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | | | - Nicole Ricker
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada.
| | - Byram W Bridle
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada.
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14
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Khojasteh‐Kaffash S, Habibzadeh A, Moghaddam S, Afra F, Samieefar N, Fateh A. Tuberculosis Trends in the Post-COVID-19 Era: Is It Going to be a Global Concern? Health Sci Rep 2025; 8:e70792. [PMID: 40406648 PMCID: PMC12094973 DOI: 10.1002/hsr2.70792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 04/14/2025] [Accepted: 04/16/2025] [Indexed: 05/26/2025] Open
Abstract
Background and Aims Tuberculosis (TB), a leading cause of death from infectious diseases, faced considerable challenges during the coronavirus disease 2019 (COVID-19) pandemic. This review examines the impact of pandemic-related disruptions, including the diversion of healthcare resources, reduced access to TB diagnostics and treatment, and declining BCG vaccination rates, on TB trends. The aim is to forecast the post-COVID-19 TB burden, identify risk factors that exacerbate transmission, and propose strategies to prevent a global resurgence. Methods This narrative review incorporates epidemiological data, modeling research, and reports from the World Health Organization and national health systems. It examines TB trends before and after COVID-19, the outcomes of coinfection, and the pandemic's impact on immunology, socioeconomic factors, and health systems. The review also compares trends in India and South Africa-two countries facing significant challenges-to those observed during the COVID-19 pandemic. Results COVID-19 disruptions in healthcare led to an 18% decrease in TB notifications in 2020, resulting in delayed diagnoses, increased household transmission, and higher mortality. Immune dysregulation, including T-cell depletion and cytokine storms, contributed to a 12.3% mortality rate in COVID-19-TB coinfections. Models predict a 5%-15% rise in TB incidence and an additional 1.4 million deaths by 2025. Individuals with HIV, diabetes, and malnutrition were particularly vulnerable. Factors such as overcrowding, air pollution, and reduced Bacillus Calmette-Guérin (BCG) coverage in endemic regions have further heightened susceptibility to TB. Conclusion COVID-19 has undone years of progress in TB control, highlighting the need for a unified health strategy. Early diagnosis, treatment of latent TB, and BCG catch-up initiatives are crucial. Strengthening health systems, addressing socioeconomic factors such as poverty and hunger, and utilizing pandemic advancements like telemedicine and vaccine research will be key to preventing a resurgence of TB. Continued financial support and international cooperation are essential to eliminating TB by 2030.
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Affiliation(s)
- Soroush Khojasteh‐Kaffash
- Network of Interdisciplinarity in Neonates and Infants (NINI)Universal Scientific Education and Research Network (USERN)TehranIran
- Student Research CommitteeSchool of Medicine, Birjand University of Medical SciencesBirjandIran
| | - Adrina Habibzadeh
- Network of Interdisciplinarity in Neonates and Infants (NINI)Universal Scientific Education and Research Network (USERN)TehranIran
- Student Research CommitteeFasa University of Medical SciencesFasaIran
| | - Sina Moghaddam
- Network of Interdisciplinarity in Neonates and Infants (NINI)Universal Scientific Education and Research Network (USERN)TehranIran
- Department of Internal Medicine, Faculty of Veterinary MedicineUniversity of TehranTehranIran
- Department of Mycobacteriology and Pulmonary ResearchPasteur Institute of IranTehranIran
| | - Fatemeh Afra
- Network of Interdisciplinarity in Neonates and Infants (NINI)Universal Scientific Education and Research Network (USERN)TehranIran
- Clinical Pharmacy DepartmentSina Hospital, Tehran University of Medical Sciences (TUMS)TehranIran
| | - Noosha Samieefar
- Network of Interdisciplinarity in Neonates and Infants (NINI)Universal Scientific Education and Research Network (USERN)TehranIran
- Pediatric Chronic Kidney Disease Research Center, Gene, Cell & Tissue Research Institute, Children's Medical CenterTehran University of Medical SciencesTehranIran
| | - Abolfazl Fateh
- Department of Mycobacteriology and Pulmonary ResearchPasteur Institute of IranTehranIran
- Microbiology Research Center (MRC)Pasteur Institute of IranTehranIran
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15
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Courtemanche O, Blais-Lecours P, Lesage S, Chabot-Roy G, Coderre L, Blanchet MR, Châteauvert N, Lellouche F, Marsolais D. Exploratory analyses of leukocyte responses in hospitalized patients treated with ozanimod following a severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection. Immunol Cell Biol 2025; 103:433-443. [PMID: 40025871 DOI: 10.1111/imcb.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/07/2025] [Accepted: 02/08/2025] [Indexed: 03/04/2025]
Abstract
Sphingosine-1-phosphate receptor 1 (S1P1) ligands effectively reduce immunopathological damage in viral pneumonia models. Specifically, S1P1 ligands inhibit cytokine storm and help preserve lung endothelial barrier integrity. We recently showed that the S1P receptor ligand ozanimod can be safely administered to hospitalized patients with coronavirus disease 2019 (COVID-19) exhibiting severe symptoms of viral pneumonia, with potential clinical benefits. Here, we extend on this study and investigate the impact of ozanimod on key features of the immune response in patients with severe COVID-19. We quantified circulating cytokine levels, peripheral immune cell numbers, proportions and activation status; we also monitored the quality of the humoral response by assessing anti-severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) antibodies. Our findings reveal that patients receiving ozanimod during acute SARS-CoV-2 infection exhibit significantly reduced numbers of circulating monocytes compared with those receiving standard care. Correspondingly, in the ozanimod-treated group, circulating levels of C-C motif ligand 2 (CCL2) were decreased. While treatment with ozanimod negatively impacted the humoral response to COVID-19 in unvaccinated patients, it did not impair the development of a robust anti-SARS-CoV-2 antibody response in vaccinated patients. These findings suggest that ozanimod influences key immune mechanisms during the acute phase of SARS-CoV-2 infection.
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Affiliation(s)
- Olivier Courtemanche
- Centre de recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, QC, Canada
| | - Pascale Blais-Lecours
- Centre de recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, QC, Canada
| | - Sylvie Lesage
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montreal, QC, Canada
| | | | - Lise Coderre
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montreal, QC, Canada
| | - Marie-Renée Blanchet
- Centre de recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, QC, Canada
- Département de Médecine, Université Laval, Quebec, QC, Canada
| | - Nathalie Châteauvert
- Centre de recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, QC, Canada
| | - François Lellouche
- Centre de recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, QC, Canada
- Département de Médecine, Université Laval, Quebec, QC, Canada
| | - David Marsolais
- Centre de recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, QC, Canada
- Département de Médecine, Université Laval, Quebec, QC, Canada
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Keskin Sarıtaş Ç, Özsüt H, Benli A, Başaran S. Examination of Risk Factors Affecting the Development of BSI and Mortality in Critically Ill COVID-19 Patients Hospitalized in Intensive Care Unit (ICU): A Single-Center Retrospective Study. J Intensive Care Med 2025; 40:547-555. [PMID: 39704100 DOI: 10.1177/08850666241305347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2024]
Abstract
Background: Various studies have shown that the incidence of BSI is greater in COVID-19 patients hospitalized in the intensive care unit (ICU). Aims: Our study aimed to determine the risk factors for BSI, mortality rates, and factors affecting mortality in adult COVID-19 patients hospitalized in the ICU. Methods: All COVID-19 patients who met the study criteria and stayed in intensive care for more than 2 days at a tertiary university hospital during the two-year pandemic period were included in the study. Logistic regression analysis was used to determine the risk factors for BSI and mortality. Results: We found that respiratory rate (RR) ≥ 30 breaths per minute at the time of admission [OR: 2.342 (95% CI: 1.12-4.897)] and antibiotic use in the month before admission ICU [OR: 3.137 (95% CI: 1.321-7.451)] were independent risk factors for BSI in COVID-19 patients. Subanalysis was also performed according to the doses of immunomodulators such as anakinra, tocilizumab, and corticosteroids, and it was found that they had no effect on the BSI (P > .05). The predominant causative pathogens were K. pneumoniae, A. baumannii and enterococci. The multidrug resistant rate among bacteria was 78%. Although their comorbidities and disease severity at the time of ICU admission were similar, patients with BSIs had a higher mortality rate (58.1 to 81.9%, P = .000). The SAPS-2 score at ICU admission [OR: 3.095 (95% CI: 1.969-4.865)] and mechanical ventilation requirement throughout the ICU admission [OR: 9.314 (95% CI: 3.878-22.37)] were found to be independent risk factors for mortality by multivariate analysis. BSI was not found to be a risk factor for mortality (> .05). Conclusions: Antibiotic use in patients with severe COVID-19 significantly increases the risk of BSI; unnecessary antibiotic use should be avoided.
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Affiliation(s)
- Çağla Keskin Sarıtaş
- Department of Infectious Diseases and Clinical Microbiology, Marmara University Training and Research Hospital, Istanbul, Turkey
| | - Halit Özsüt
- Department of Infectious Diseases and Clinical Microbiology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Aysun Benli
- Department of Infectious Diseases and Clinical Microbiology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Seniha Başaran
- Department of Infectious Diseases and Clinical Microbiology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
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17
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Meseldžić N, Prnjavorac B, Dujić T, Malenica M, Prnjavorac L, Bedak O, Imamović-Kadrić S, Marjanović D, Bego T. Insights into biochemical, hematological, and coagulation parameters and their association with COVID-19 severity within four patients cohort from Bosnia and Herzegovina. Technol Health Care 2025:9287329251327481. [PMID: 40302487 DOI: 10.1177/09287329251327481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025]
Abstract
IntroductionCOVID-19, caused by the SARS-CoV-2 virus, has resulted in a global public health crisis with a wide spectrum of clinical manifestations, ranging from asymptomatic infections to severe pneumonia. This study explores the association between various biomarkers and COVID-19 progression, aiming to identify early indicators of disease severity and enhance patient management.Materials and MethodsThe study included 750 confirmed COVID-19 patients categorized into four groups based on disease severity. Patients were recruited at the General Hospital in Tešanj, Bosnia and Herzegovina. All biochemical, hematological and coagulation parameters were analyzed using standard IFCC protocols.ResultsThe study identified significant differences in biochemical, hematological, and coagulation biomarkers across varying COVID-19 severities. Key markers such as C-reactive protein (CRP), D-dimer, lymphocyte count, erythrocyte sedimentation rate (ESR), and platelet count were analyzed. Elevated CRP and D-dimer were strongly linked to severe cases, while decreased lymphocyte count, elevated ESR, and platelet abnormalities were also associated with increased disease severity.ConclusionsOur study highlights the vital role of specific biochemical, hematological and coagulation parameters in predicting COVID-19 severity. Integrating these findings into clinical practice could enhance timely risk stratification, early intervention, and improved outcomes for affected individuals.
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Affiliation(s)
- Neven Meseldžić
- Department of Pharmaceutical biochemistry and laboratory diagnostics, University of Sarajevo, Faculty of Pharmacy, Sarajevo, Bosnia and Herzegovina
| | | | - Tanja Dujić
- Department of Pharmaceutical biochemistry and laboratory diagnostics, University of Sarajevo, Faculty of Pharmacy, Sarajevo, Bosnia and Herzegovina
| | - Maja Malenica
- Department of Pharmaceutical biochemistry and laboratory diagnostics, University of Sarajevo, Faculty of Pharmacy, Sarajevo, Bosnia and Herzegovina
| | | | - Omer Bedak
- General Hospital Tešanj, Tešanj, Bosnia and Herzegovina
| | - Selma Imamović-Kadrić
- Department of Pharmaceutical biochemistry and laboratory diagnostics, University of Sarajevo, Faculty of Pharmacy, Sarajevo, Bosnia and Herzegovina
| | - Damir Marjanović
- Institute for Anthropological Research, Zagreb, Croatia
- Department of Genetics and Bioengineering, International Burch University, Sarajevo, Bosnia and Herzegovina
- Faculty of Biotechnology and Drug Development, University of Rijeka, Rijeka, Croatia
| | - Tamer Bego
- Department of Pharmaceutical biochemistry and laboratory diagnostics, University of Sarajevo, Faculty of Pharmacy, Sarajevo, Bosnia and Herzegovina
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18
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Sun Q, Zhao R, Li S, Zhou W, Zhang J, Pang B, Ding S, Bao L, Geng Z, Xie R, Xie D, Cui X, Guo S, Sun J. Verbenalin protects against coronavirus pneumonia by promoting host immune homeostasis: Evidences for its mechanism of action. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 143:156820. [PMID: 40347923 DOI: 10.1016/j.phymed.2025.156820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 04/22/2025] [Accepted: 04/29/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Coronavirus has caused high-mortality viral pneumonia worldwide. The pathogenesis is characterized by hyperinflammatory reactions resulting from immune homeostasis dysregulation. Verbenalin, an iridoid glucoside derived from Verbena officinalis L., is widely used in Traditional Chinese Medicine (TCM) clinical practice for its antioxidant, anti-inflammatory and antiviral properties. PURPOSE This study aimed to investigate the pharmacological effects and underlying mechanisms of verbenalin on coronavirus pneumonia both in vivo and in vitro. METHODS A coronavirus pneumonia mouse model and macrophage injury models, including mouse alveolar macrophage cell line (MH-S) cells and primary macrophages, were established to initially confirm the antiviral effects of verbenalin. Time-resolved proteomic were then employed to uncover proteomic changes and identify potential therapeutic targets for coronavirus treatment. Subsequently, flow cytometry and Western blot were employed to investigate verbenalin's effects on NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. Additionally, the targeting regulation of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) / E3 ubiquitin ligase Parkin (Parkin) pathway by verbenalin was validated through molecular docking, surface plasmon resonance (SPR), immunofluorescent staining, RNA interference (RNAi), and mitophagy inhibition both in vivo and in vitro. RESULTS Verbenalin reduced cell injury and inflammation in Human coronavirus 229E (HCoV-229E)-infected macrophages and improved lung inflammation in mice. Proteomics analysis highlighted the roles of nucleotide-binding oligomerization domain (NOD)-like receptor signaling and mitophagy pathways in coronavirus pneumonia. Verbenalin bound strongly to PINK1 and Parkin proteins, increased mitochondrial membrane potential (MMP), decreased mitochondrial reactive oxygen species (mtROS) levels, reduced the opening of mitochondrial permeability transition pore (MPTP), maintained mitochondrial mass, promoted mitophagy flux, upregulated the expression of PINK1, Parkin, and microtubule-associated protein 1A/1B-light chain 3BII (LC3BII). Additionally, verbenalin inhibited the activation of the NLRP3 inflammasome and downregulated the expression of Interleukin-1 beta (IL-1β), cysteine aspartate-specific protease 1 (caspase-1), and gasdermin D (GSDMD) both in vivo and in vitro. Furthermore, treatment with a mitophagy inhibitor and RNAi attenuated the inhibitory effects of verbenalin on NLRP3 activation, confirming the involvement of the PINK1/Parkin/NLRP3 pathway in verbenalin's protective effects. CONCLUSION Verbenalin enhances PINK1/Parkin-mediated mitophagy to suppress NLRP3 activation, thereby promoting immune homeostasis and mitigating HCoV-229E-induced inflammation.
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Affiliation(s)
- Qiyue Sun
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China
| | - Ronghua Zhao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China
| | - Shuran Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China
| | - Weiqin Zhou
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Jingsheng Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China
| | - Bo Pang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China
| | - Shilan Ding
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China
| | - Lei Bao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China
| | - Zihan Geng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China
| | - Rui Xie
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China
| | - Dan Xie
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China
| | - Xiaolan Cui
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China.
| | - Shanshan Guo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China.
| | - Jing Sun
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Chaoyang District, Beijing 100029, China.
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19
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Guziejko K, Moniuszko-Malinowska A, Flisiak R, Czupryna P, Sołomacha S, Sowa P, Dubatówka M, Łapińska M, Kiszkiel Ł, Szczerbiński Ł, Laskowski PP, Alimowski M, Trojan G, Kamiński KA. Assessment of the Abnormalities in Chest Computed Tomography and Pulmonary Function Test in Convalescents Six Months After COVID-19. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:823. [PMID: 40428781 PMCID: PMC12113045 DOI: 10.3390/medicina61050823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2025] [Revised: 04/22/2025] [Accepted: 04/26/2025] [Indexed: 05/29/2025]
Abstract
Background: Despite the multiple waves of the COVID-19 pandemic, follow-up strategies for recovered patients remain inconclusive. This study aimed to evaluate chest computed tomography (CT) and pulmonary function test (PFT) abnormalities in convalescents six months after COVID-19 and to compare these findings with those from a representative population cohort. The goal was to support more individualized pulmonary management of post-COVID-19 sequelae. Methods: This study population consisted of 2 groups: I-232 post-COVID-19 patients and II-543 patients from a population cohort. Chest CT was performed during the acute phase of COVID-19 and six months after. The PFTs were conducted six months after COVID-19. Results: There were no significant differences in FEV1, FVC, TLC, and DLCO in the two study groups. A singular GGO in 24 patients (20%), a crazy paving pattern in 1 patient (0.8%), thickening of interlobular septa in 4 patients (3.5%), consolidations in 4 patients (3.5%), traction bronchiectasis in 6 patients (5%), fibrosis in 6 patients (5%), and singular nodular densities in 68 patients (58%) were observed in chest CT 6 months after COVID-19. Most radiological abnormalities were clinically insignificant and did not require further diagnostic evaluation. No significant differences in chest CT and PFT six months after infection were observed between patients differing in the severity of inflammation during the acute disease or SARS-CoV-2 variant. Conclusions: The majority of chest CT abnormalities resolved within six months of recovery, regardless of SARS-CoV-2 variant or initial disease severity. Pulmonary function tests should be prioritized in post-COVID-19 follow-up, as PFT results in convalescents were comparable to those observed in the general population.
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Affiliation(s)
- Katarzyna Guziejko
- 2nd Department of Lung Diseases, Lung Cancer and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Anna Moniuszko-Malinowska
- Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, 15-089 Bialystok, Poland;
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, 15-089 Bialystok, Poland;
| | - Piotr Czupryna
- Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, 15-089 Bialystok, Poland;
| | - Sebastian Sołomacha
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, 15-089 Bialystok, Poland; (S.S.); (P.S.); (M.D.); (M.Ł.)
| | - Paweł Sowa
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, 15-089 Bialystok, Poland; (S.S.); (P.S.); (M.D.); (M.Ł.)
| | - Marlena Dubatówka
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, 15-089 Bialystok, Poland; (S.S.); (P.S.); (M.D.); (M.Ł.)
| | - Magda Łapińska
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, 15-089 Bialystok, Poland; (S.S.); (P.S.); (M.D.); (M.Ł.)
| | - Łukasz Kiszkiel
- Society and Cognition Unit, University of Bialystok, 15-328 Bialystok, Poland; (Ł.K.); (P.P.L.)
| | - Łukasz Szczerbiński
- Clinical Research Centre, Medical University of Bialystok, 15-089 Bialystok, Poland;
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Piotr Paweł Laskowski
- Society and Cognition Unit, University of Bialystok, 15-328 Bialystok, Poland; (Ł.K.); (P.P.L.)
| | - Maciej Alimowski
- Doctoral School of Social Sciences, University of Bialystok, 15-328 Bialystok, Poland;
| | - Gabriela Trojan
- Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, 15-089 Bialystok, Poland;
| | - Karol Adam Kamiński
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, 15-089 Bialystok, Poland; (S.S.); (P.S.); (M.D.); (M.Ł.)
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20
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Lizarazo-Taborda MDR, Vega-Magaña N, Díaz-Palomera CD, Villegas-Pineda JC, Godínez-Rubí M, Bayardo-González RA, Ramírez-de-Arellano A, Pereira-Suárez AL. A comparative analysis of estrogen receptors, ACE2 and cytokines in pre-and postmenopausal women and men with COVID-19. Front Public Health 2025; 13:1554024. [PMID: 40356822 PMCID: PMC12066641 DOI: 10.3389/fpubh.2025.1554024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Accepted: 03/25/2025] [Indexed: 05/15/2025] Open
Abstract
The pandemic of Coronavirus Disease 2019 (COVID-19) has a significant impact on older individuals, those with comorbidities, and a bias toward males. Mortality, associated with an exacerbated immune response by proinflammatory cytokines, suggests potential hormonal influences in this scenario. The objective of this research was to analyze the expression of Estrogen Receptor α (ERα), Estrogen Receptor β (ERβ), G Protein-Coupled Estrogen Receptor (GPER), and the Angiotensin-Converting Enzyme 2 (ACE2) receptor, as well as their relationship with the viral load of SARS-CoV-2 and serum cytokine levels in three demographic groups of unvaccinated individuals diagnosed with COVID-19: premenopausal women, postmenopausal women, and men. The presence and expression of ERα, ERβ, and GPER, along with the ACE2 receptor, were analyzed by immunofluorescence assays in cells obtained from nasopharyngeal swabs of individuals with confirmed COVID-19 through RT-qPCR testing. Additionally, serum cytokine levels were evaluated using a chemiluminescent microparticle immunoassay. The results highlighted notable disparities in the expression of ERα and ACE2, as well as a higher expression of IL-8 and MIP-1β in the premenopausal women group compared to postmenopausal women and men. These findings suggest that in premenopausal women with COVID-19, the elevated expression of ERα and ACE2 could play a protective role, strengthening the antiviral immune response. The importance of exploring the complex hormonal and molecular influences in the pathogenesis of COVID-19 is emphasized, underscoring the need for additional research to better understand the factors determining severity and immune response in different demographic groups.
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Affiliation(s)
- Mélida Del Rosario Lizarazo-Taborda
- Maestría en Microbiología Médica, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
- Laboratorio de Investigación en Cáncer e Infecciones, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Natali Vega-Magaña
- Laboratorio de Investigación en Cáncer e Infecciones, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Carlos Daniel Díaz-Palomera
- Laboratorio de Investigación en Cáncer e Infecciones, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Julio César Villegas-Pineda
- Laboratorio de Investigación en Cáncer e Infecciones, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Marisol Godínez-Rubí
- Departamento de Morfología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
- Laboratorio de Patología Diagnóstica e Inmunohistoquímica, Centro de Investigación y Diagnóstico en Patología, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Rubén Alberto Bayardo-González
- Departamento de Clínicas Odontológicas Integrales, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Adrián Ramírez-de-Arellano
- Laboratorio de Investigación en Cáncer e Infecciones, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Ana Laura Pereira-Suárez
- Laboratorio de Investigación en Cáncer e Infecciones, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
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21
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da Silva-Neto PV, de Carvalho JCS, Toro DM, Oliveira BTM, Cominal JG, Castro RC, Almeida MA, Prado CM, Arruda E, Frantz FG, Ramos AP, Ciancaglini P, Martins RB, da Silveira JC, Almeida F, Malmegrim KCR, Sorgi CA. TREM-1-Linked Inflammatory Cargo in SARS-CoV-2-Stimulated Macrophage Extracellular Vesicles Drives Cellular Senescence and Impairs Antibacterial Defense. Viruses 2025; 17:610. [PMID: 40431622 PMCID: PMC12115590 DOI: 10.3390/v17050610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/29/2025] [Accepted: 04/19/2025] [Indexed: 05/29/2025] Open
Abstract
The COVID-19 pandemic, caused by SARS-CoV-2, has significantly affected global health, with severe inflammatory responses leading to tissue damage and persistent symptoms. Macrophage-derived extracellular vesicles (EVs) are involved in the modulation of immune responses, but their involvement in SARS-CoV-2-induced inflammation and senescence remains unclear. Triggering receptors expressed on myeloid cell-1 (TREM-1) are myeloid cell receptors that amplify inflammation, described as a biomarker of the severity and mortality of COVID-19. This study investigated the composition and effects of macrophage-derived EVs stimulated by SARS-CoV-2 (MφV-EVs) on the recipient cell response. Our results, for the first time, show that SARS-CoV-2 stimulation modifies the cargo profile of MφV-EVs, enriching them with TREM-1 and miRNA-155 association, along with MMP-9 and IL-8/CXCL8. These EVs carry senescence-associated secretory phenotype (SASP) components, promote cellular senescence, and compromise antibacterial defenses upon internalization. Our findings provide evidence that MφV-EVs are key drivers of inflammation and immune dysfunction, underscoring their potential as therapeutic targets in COVID-19.
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Affiliation(s)
- Pedro V. da Silva-Neto
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto-FFCLRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-901, SP, Brazil; (P.V.d.S.-N.); (J.C.S.d.C.); (J.G.C.); (A.P.R.); (P.C.)
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-903, SP, Brazil; (R.C.C.); (F.G.F.); (R.B.M.); (K.C.R.M.)
| | - Jonatan C. S. de Carvalho
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto-FFCLRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-901, SP, Brazil; (P.V.d.S.-N.); (J.C.S.d.C.); (J.G.C.); (A.P.R.); (P.C.)
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-903, SP, Brazil; (R.C.C.); (F.G.F.); (R.B.M.); (K.C.R.M.)
| | - Diana M. Toro
- Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirão Preto 14049-900, SP, Brazil; (D.M.T.); (E.A.)
| | - Bianca T. M. Oliveira
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirão Preto 14049-900, SP, Brazil; (B.T.M.O.); (F.A.)
| | - Juçara G. Cominal
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto-FFCLRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-901, SP, Brazil; (P.V.d.S.-N.); (J.C.S.d.C.); (J.G.C.); (A.P.R.); (P.C.)
| | - Ricardo C. Castro
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-903, SP, Brazil; (R.C.C.); (F.G.F.); (R.B.M.); (K.C.R.M.)
| | - Maria A. Almeida
- Departamento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos-FZEA, Universidade de São Paulo-USP, Pirassununga 13635-900, SP, Brazil; (M.A.A.); (C.M.P.); (J.C.d.S.)
| | - Cibele M. Prado
- Departamento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos-FZEA, Universidade de São Paulo-USP, Pirassununga 13635-900, SP, Brazil; (M.A.A.); (C.M.P.); (J.C.d.S.)
| | - Eurico Arruda
- Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirão Preto 14049-900, SP, Brazil; (D.M.T.); (E.A.)
| | - Fabiani G. Frantz
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-903, SP, Brazil; (R.C.C.); (F.G.F.); (R.B.M.); (K.C.R.M.)
| | - Ana P. Ramos
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto-FFCLRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-901, SP, Brazil; (P.V.d.S.-N.); (J.C.S.d.C.); (J.G.C.); (A.P.R.); (P.C.)
| | - Pietro Ciancaglini
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto-FFCLRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-901, SP, Brazil; (P.V.d.S.-N.); (J.C.S.d.C.); (J.G.C.); (A.P.R.); (P.C.)
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirão Preto 14049-900, SP, Brazil; (B.T.M.O.); (F.A.)
| | - Ronaldo B. Martins
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-903, SP, Brazil; (R.C.C.); (F.G.F.); (R.B.M.); (K.C.R.M.)
| | - Juliano C. da Silveira
- Departamento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos-FZEA, Universidade de São Paulo-USP, Pirassununga 13635-900, SP, Brazil; (M.A.A.); (C.M.P.); (J.C.d.S.)
| | - Fausto Almeida
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirão Preto 14049-900, SP, Brazil; (B.T.M.O.); (F.A.)
| | - Kelen C. R. Malmegrim
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-FCFRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-903, SP, Brazil; (R.C.C.); (F.G.F.); (R.B.M.); (K.C.R.M.)
| | - Carlos A. Sorgi
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto-FFCLRP, Universidade de São Paulo-USP, Ribeirão Preto 14040-901, SP, Brazil; (P.V.d.S.-N.); (J.C.S.d.C.); (J.G.C.); (A.P.R.); (P.C.)
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto-FMRP, Universidade de São Paulo-USP, Ribeirão Preto 14049-900, SP, Brazil; (B.T.M.O.); (F.A.)
- Programa de Pós-graduação em Imunologia Básica e Aplicada-PPGIBA, Instituto de Ciências Biológicas, Universidade Federal do Amazonas-UFAM, Manaus 69080-900, AM, Brazil
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22
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Chatterjee D, Kurup D, Smeyne RJ. Environmental exposures and familial background alter the induction of neuropathology and inflammation after SARS-CoV-2 infection. NPJ Parkinsons Dis 2025; 11:86. [PMID: 40268936 PMCID: PMC12019605 DOI: 10.1038/s41531-025-00925-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 03/27/2025] [Indexed: 04/25/2025] Open
Abstract
Post-infection sequela of several viruses have been linked with Parkinson's disease (PD). Here, we investigated whether mice infected with SARS-CoV-2 alone or in combination with two putative Parkinsonian toxins, MPTP and paraquat, increased the susceptibility to develop Parkinsonian pathology. We also examined if G2019S LRRK2 mice had any change in sensitivity to SARS-CoV-2 as well as if vaccination against this virus altered any neuropathology. Infection with WA-1/2020 or Omicron B1.1.529 strains sensitized both WT and G2019S LRRK2 mice to the neuropathological effects of a subtoxic exposure to MPTP, but not paraquat. These neuropathologies were rescued in WT mice vaccinated with mRNA- or protein-based SARS-CoV-2 vaccines. However, G2019S LRRK2 mutant mice were only protected with the protein-based vaccine. These results highlight the role of both environmental exposures and familial background on the development of Parkinsonian pathology secondary to viral infection and the benefit of vaccines in reducing these risks.
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Affiliation(s)
- Debotri Chatterjee
- Department of Neurobiology, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA, 19107, USA
| | - Drishya Kurup
- Department of Microbiology and Immunology, Thomas Jefferson University, 233 S 10th Street, Philadelphia, PA, 19107, USA
- Jefferson Center for Vaccines and Pandemic Preparedness, 233 S 10th Street, Philadelphia, PA, 19107, USA
| | - Richard Jay Smeyne
- Department of Neurobiology, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA, 19107, USA.
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23
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Mayer MG, Fischer T. Shared Mechanisms of Blood-Brain Barrier Dysfunction and Neuroinflammation in Coronavirus Disease 2019 and Alzheimer Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00118-X. [PMID: 40254131 DOI: 10.1016/j.ajpath.2025.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/14/2025] [Accepted: 03/21/2025] [Indexed: 04/22/2025]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the virus's impact on the central nervous system and its potential to exacerbate neurodegenerative diseases, like Alzheimer disease (AD). Emerging evidence suggests that SARS-CoV-2 infection contributes to chronic neuroinflammation, a key driver in the etiopathogenesis of AD. Shared mechanisms, including blood-brain barrier (BBB) dysfunction, systemic inflammation, and activation of immune pathways, may link SARS-CoV-2 infection to AD onset and/or progression, particularly among vulnerable individuals, such as those of advanced age. This review explores convergent pathways involving the renin-angiotensin-aldosterone system, Wnt/β-catenin signaling, NF-κB activation, and interferon signaling, focusing on their roles in BBB integrity and neuroinflammation. SARS-CoV-2-mediated angiotensin-converting enzyme 2 depletion disrupts renin-angiotensin-aldosterone system homeostasis, favoring proinflammatory signaling that parallels vascular dysfunction in AD. Dysregulation of Wnt/β-catenin signaling exacerbates BBB permeability, whereas NF-κB and interferon pathways contribute to BBB breakdown and propagate central nervous system inflammation via endothelial and immune cell activation. These interactions may amplify prodromal AD pathology and/or initiate AD pathogenesis. By identifying mechanistic overlaps between COVID-19 and AD, this review underlines the need for therapeutic strategies targeting shared pathways of inflammation and BBB dysfunction. Understanding these connections is critical for mitigating the long-term neurologic sequelae of COVID-19 and reducing the burden of AD.
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Affiliation(s)
| | - Tracy Fischer
- Tulane National Primate Research Center, Covington, Louisiana; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana.
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24
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Sellarès-Nadal J, Espinosa-Pereiro J, Burgos J, Falcó V, Guillén-Del-Castillo A, Augustin S, Bañares-Sánchez J, Prio-Ruatg A, Martínez-Valle F, Kirkegaard-Biosca C, Sánchez-Montalvá A. Efficacy of tocilizumab for hospitalized patients with COVID-19 pneumonia and high IL-6 levels: A randomized controlled trial. Infection 2025:10.1007/s15010-025-02506-y. [PMID: 40232661 DOI: 10.1007/s15010-025-02506-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 03/04/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND The objective of this clinical trial is to evaluate the efficacy and safety of IL-6 driven personalized treatment strategy with tocilizumab in patients with severe COVID-19 pneumonia. TRIAL DESIGN Randomized, controlled, open-label, single-center trial of a tocilizumab treatment strategy in adult patients hospitalized with severe COVID-19 pneumonia and IL-6 serum levels > 40 pg/mL. METHODS Patients were randomized 1:1 to receive standard of care (SOC) or SOC plus one dose of tocilizumab. The primary outcome was death or need for invasive mechanical ventilation (IMV) within 28 days after randomization. Secondary outcomes included ICU admission, days on IMV and hospital stay. A meta-analysis of clinical trials to evaluate the effect of tocilizumab on mortality and need of IMV in patients with COVID-19 pneumonia was performed. RESULTS Sixty-two patients were included: 30 in the SOC arm and 32 in the standard-treatment plus tocilizumab arm. The primary outcome occurred in 12.9% in the tocilizumab arm and 32.3% in the SOC arm(p = 0.068). There was a trend towards fewer days on IMV (7.5 vs 19.5 days, p = 0.073) and a shorter hospital stay (4 vs 8 days, p = 0.134) in the tocilizumab group. No serious adverse events were reported. The meta-analysis revealed a RR for death or IMV of 0.83 (95% CI: 0.77-0.89) in patients receiving tocilizumab, compared to patients receiving SOC. CONCLUSION Tocilizumab could be effective to prevent death or IMV in patients with severe COVID-19 pneumonia and high IL-6 serum levels. Safety profile of tocilizumab does not arise major concern in patients with severe COVID19.
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Affiliation(s)
- Júlia Sellarès-Nadal
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Infectious Diseases Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain
- Malalties Infeccioses Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Juan Espinosa-Pereiro
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Infectious Diseases Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain
- Malalties Infeccioses Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Infectious Diseases Department, International Health Unit Vall d'Hebron-Drassanes, Vall d'Hebron University Hospital, PROSICS Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Joaquín Burgos
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
- Infectious Diseases Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain.
- Malalties Infeccioses Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain.
| | - Vicenç Falcó
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Infectious Diseases Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain
- Malalties Infeccioses Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Alfredo Guillén-Del-Castillo
- Internal Medicine Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Salvador Augustin
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Juan Bañares-Sánchez
- Hepatology Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Alba Prio-Ruatg
- Hepatology Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Ferran Martínez-Valle
- Internal Medicine Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Cristina Kirkegaard-Biosca
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Infectious Diseases Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain
- Malalties Infeccioses Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Adrián Sánchez-Montalvá
- Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Infectious Diseases Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain
- Malalties Infeccioses Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Infectious Diseases Department, International Health Unit Vall d'Hebron-Drassanes, Vall d'Hebron University Hospital, PROSICS Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
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25
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Astroth C, Shah KS, Agrawal S, Agrawal A. Weathering the Storm: How Age and Biologics Influence the COVID-19 Cytokine Surge. Pathogens 2025; 14:346. [PMID: 40333142 PMCID: PMC12030216 DOI: 10.3390/pathogens14040346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/01/2025] [Accepted: 04/01/2025] [Indexed: 05/09/2025] Open
Abstract
SARS-CoV-2, first identified in December 2019, caused a global pandemic, resulting in over 6.8 million deaths by March 2023. The elderly, or individuals over 65, accounted for the majority of COVID-19 deaths, with 81% of fatalities in the US in 2020 occurring in this group. Beyond mortality, aging populations are also at higher risk of long-term cardiovascular complications and acute respiratory distress syndrome (ARDS). Although these outcomes may be influenced by comorbidities common in the elderly, age has been found to be a standalone risk factor for severe COVID-19 infection. Therefore, investigating age-related factors in COVID-19 outcomes is crucial in protecting this vulnerable group. Of particular interest is the cytokine storm phenomenon, an excessive inflammatory response that contributes to severe COVID-19 symptoms, including ARDS and cardiovascular damage. Elevated levels of multiple cytokines are common in severe cases of COVID-19. We propose that changes that occur to cytokine profiles as we age may contribute to these aberrant inflammatory responses. This review specifically explored the interleukin class cytokines IL-1, IL-6, IL-17, and IL-23 and considered the potential of biologics targeting these cytokines to alleviate severe outcomes in both COVID-19 and aging individuals.
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Affiliation(s)
| | | | | | - Anshu Agrawal
- Division of Basic and Clinical Immunology, Department of Medicine, University of California Irvine, Irvine, CA 92697, USA; (C.A.); (K.S.S.); (S.A.)
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26
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Yang OO. The immunopathogenesis of SARS-CoV-2 infection: Overview of lessons learned in the first 5 years. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf033. [PMID: 40180332 DOI: 10.1093/jimmun/vkaf033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 02/11/2025] [Indexed: 04/05/2025]
Abstract
This review provides a broad overview of lessons learned in the five years since COVID-19 was identified. It is a bimodal disease, starting with an initially virus-driven phase, followed by resolution or ensuing inappropriate immune activation causing severe inflammation that is no longer strictly virus dependent. Humoral immunity is beneficial for preventing or attenuating the early stage, without benefit once the later stage begins. Neutralizing antibodies elicited by natural infection or vaccination are short-lived and highly vulnerable to viral sequence variation. By contrast, cellular immunity, particularly the CD8+ T cell arm, has a role in preventing or attenuating severe disease, is far less susceptible to viral variation, and is longer-lived than antibodies. Finally, an ill-defined phenomenon of prolonged symptoms after acute infection, termed "long COVID," is poorly understood but may involve various immunologic defects that are hyperactivating or immunosuppressive. Remaining issues include needing to better understand the immune dysregulation of severe disease to allow more tailored therapeutic interventions, developing antibody strategies that cope with the viral spike sequence variability, prolonging vaccine efficacy, and unraveling the mechanisms of long COVID to design therapeutic approaches.
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Affiliation(s)
- Otto O Yang
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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27
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Jacob IB, Lawal AO, Mahmoud SS, Kopsack EM, Reynolds ES, Meng Q, Fan H, Massa PT, Thangamani S, Jia H, Wang G. Differential immunoregulation by human surfactant protein A variants determines severity of SARS-CoV-2-induced lung disease. Front Immunol 2025; 16:1462278. [PMID: 40242753 PMCID: PMC12000003 DOI: 10.3389/fimmu.2025.1462278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 03/10/2025] [Indexed: 04/18/2025] Open
Abstract
Introduction COVID-19 remains a significant threat to public health globally. Infection in some susceptible individuals causes life-threatening acute lung injury (ALI/ARDS) and/or death. Human surfactant protein A (SP-A) is a C-type lectin expressed in the lung and other mucosal tissues, and it plays a critical role in host defense against various pathogens. The human SP-A genes (SFTPA1 and SFTPA2) are highly polymorphic and comprise several common genetic variants, i.e., SP-A1 (variants 6A2, 6A4) and SP-A2 (variants 1A0, 1A3). Here, we elucidated the differential antiviral and immunoregulatory roles of SP-A variants in response to SARS-CoV-2 infection in vivo. Methods Six genetically-modified mouse lines, expressing both hACE2 (SARS-CoV-2 receptor) and individual SP-A variants: (hACE2/6A2 (6A2), hACE2/6A4 (6A4), hACE2/1A0 (1A0), and hACE2/1A3 (1A3), one SP-A knockout (hACE2/SP-A KO (KO) and one hACE2/mouse SP-A (K18) mice, were challenged intranasally with 103 PFU SARS-CoV-2 or MEM medium (Sham). Results Infected KO and 1A0 mice had more weight loss and mortality compared to other mouse lines. Relative to other infected mouse lines, a more severe ALI was observed in KO, 1A0, and 6A2 mice. Reduced viral titers were generally observed in the lungs of infected SP-A mice relative to KO mice. Transcriptomic analysis revealed an upregulation in genes that play central roles in immune responses such as MyD88, Stat3, IL-18, and Jak2 in the lungs of KO and 1A0 mice. However, Mapk1 was significantly downregulated in 6A2 versus 1A0 mice. Analysis of biological pathways identified those involved in lung host defense and innate immunity, including pathogen-induced cytokine, NOD1/2, and Trem1 signaling pathways. Consistent with the transcriptomic data, levels of cytokines and chemokines such as G-CSF, IL-6, and IL-1β were comparatively higher in the lungs and sera of KO and 1A0 mice with the highest mortality rate. Furthermore, we observed the complexity of COVID-19, such as the difference between lung and systemic immune response to viral infection and of viral load and mortality among SP-A variants in this model. Conclusion These findings demonstrate that human SP-A variants differentially modulate SARS-CoV-2-induced lung injury and disease severity by differentially inhibiting viral infectivity and regulating immune-related gene expressions.
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Affiliation(s)
- Ikechukwu B. Jacob
- Department of Surgery, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
- Department of Microbiology and Immunology, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
| | - Akinkunmi O. Lawal
- Department of Surgery, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
- Department of Microbiology and Immunology, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
| | - Salma S. Mahmoud
- Department of Surgery, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
| | - Emerson M. Kopsack
- Department of Surgery, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
| | - Erin S. Reynolds
- Department of Microbiology and Immunology, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
| | - Qinghe Meng
- Department of Surgery, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
| | - Hongkuan Fan
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Paul T. Massa
- Department of Microbiology and Immunology, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
- Department of Neurology, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
| | - Saravanan Thangamani
- Department of Microbiology and Immunology, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
| | - Hongpeng Jia
- Department of Surgery, Johns-Hopkins University, Baltimore, MD, United States
| | - Guirong Wang
- Department of Surgery, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
- Department of Microbiology and Immunology, The State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
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28
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Li W, Zhang Z, Kumar S, Botey-Bataller J, Zoodsma M, Ehsani A, Zhan Q, Alaswad A, Zhou L, Grondman I, Koeken V, Yang J, Wang G, Volland S, Crişan TO, Joosten LAB, Illig T, Xu CJ, Netea MG, Li Y. Single-cell immune aging clocks reveal inter-individual heterogeneity during infection and vaccination. NATURE AGING 2025; 5:607-621. [PMID: 40044970 PMCID: PMC12003178 DOI: 10.1038/s43587-025-00819-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 01/24/2025] [Indexed: 04/18/2025]
Abstract
Aging affects human immune system functionality, increasing susceptibility to immune-mediated diseases. While gene expression programs accurately reflect immune function, their relationship with biological immune aging and health status remains unclear. Here we developed robust, cell-type-specific aging clocks (sc-ImmuAging) for the myeloid and lymphoid immune cell populations in circulation within peripheral blood mononuclear cells, using single-cell RNA-sequencing data from 1,081 healthy individuals aged from 18 to 97 years. Application of sc-ImmuAging to transcriptome data of patients with COVID-19 revealed notable age acceleration in monocytes, which decreased during recovery. Furthermore, inter-individual variations in immune aging induced by vaccination were identified, with individuals exhibiting elevated baseline interferon response genes showing age rejuvenation in CD8+ T cells after BCG vaccination. sc-ImmuAging provides a powerful tool for decoding immune aging dynamics, offering insights into age-related immune alterations and potential interventions to promote healthy aging.
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Affiliation(s)
- Wenchao Li
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Zhenhua Zhang
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Saumya Kumar
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Javier Botey-Bataller
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Martijn Zoodsma
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Ali Ehsani
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Qiuyao Zhan
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Ahmed Alaswad
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Liang Zhou
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Inge Grondman
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Valerie Koeken
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
- Research Centre Innovations in Care, Rotterdam University of Applied Sciences, Rotterdam, The Netherlands
| | - Jian Yang
- The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Gang Wang
- The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Sonja Volland
- Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
| | - Tania O Crişan
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Thomas Illig
- Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hanover Medical School, Hannover, Germany
- Lower Saxony center for artificial intelligence and causal methods in medicine (CAIMed), Hannover, Germany
| | - Cheng-Jian Xu
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
- Department for Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
| | - Yang Li
- Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
- Cluster of Excellence RESIST (EXC 2155), Hanover Medical School, Hannover, Germany.
- Lower Saxony center for artificial intelligence and causal methods in medicine (CAIMed), Hannover, Germany.
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29
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Song Y, Lu J, Qin P, Chen H, Chen L. Interferon-I modulation and natural products: Unraveling mechanisms and therapeutic potential in severe COVID-19. Cytokine Growth Factor Rev 2025; 82:18-30. [PMID: 39261232 DOI: 10.1016/j.cytogfr.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 08/20/2024] [Indexed: 09/13/2024]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a significant global public health threat, particularly to older adults, pregnant women, and individuals with underlying chronic conditions. Dysregulated immune responses to SARS-CoV-2 infection are believed to contribute to the progression of COVID-19 in severe cases. Previous studies indicates that a deficiency in type I interferon (IFN-I) immunity accounts for approximately 15 %-20 % of patients with severe pneumonia caused by COVID-19, highlighting the potential therapeutic importance of modulating IFN-I signals. Natural products and their derivatives, due to their structural diversity and novel scaffolds, play a crucial role in drug discovery. Some of these natural products targeting IFN-I have demonstrated applications in infectious diseases and inflammatory conditions. However, the immunomodulatory potential of IFN-I in critical COVID-19 pneumonia and the natural compounds regulating the related signal pathway remain not fully understood. In this review, we offer a comprehensive assessment of the association between IFN-I and severe COVID-19, exploring its mechanisms and integrating information on natural compounds effective for IFN-I regulation. Focusing on the primary targets of IFN-I, we also summarize the regulatory mechanisms of natural products, their impact on IFNs, and their therapeutic roles in viral infections. Collectively, by synthesizing these findings, our goal is to provide a valuable reference for future research and to inspire innovative treatment strategies for COVID-19.
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Affiliation(s)
- Yuheng Song
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jiani Lu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Pengcheng Qin
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; School of Pharmacy, Henan University, Kaifeng 475001, China
| | - Hongzhuan Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai 200032, China
| | - Lili Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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30
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Zhou F, Guo Y, Li W, Hu Y, Yang L, Fu S, Bao X, Tong H, Ye Y, Ding Z. Tetrastigma hemsleyanum polysaccharide protects against "two-hit" induced severe pneumonia via TLR4/NF-κB signaling pathway. Int J Biol Macromol 2025; 303:140639. [PMID: 39909274 DOI: 10.1016/j.ijbiomac.2025.140639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 01/24/2025] [Accepted: 02/01/2025] [Indexed: 02/07/2025]
Abstract
Severe pneumonia, frequently accompanied by cytokine storms, stands as a perilous respiratory condition with alarmingly high mortality rates. Tetrastigma hemsleyanum polysaccharide (THP), a pivotal constituent derived from Tetrastigma hemsleyanum Diels et Gilg (TH), has demonstrated efficacy in treating lung inflammation. However, its precise efficacy and underlying mechanisms in the context of severe pneumonia remain elusive. Our research aims to elucidate THP's protective effects in a "two-hit" severe pneumonia model. Our observations indicate that THP administration markedly shields the lungs from injury, reduces pulmonary apoptosis, balances the formation of immune thrombus and alleviates oxidative stress in pneumonia-induced mice. Furthermore, THP significantly decreases the levels of pro-inflammatory cytokines, suggesting its robust anti-inflammatory capabilities. Notably, THP also plays a crucial role in normalizing gut microbiota imbalance, which is vital in the pathogenesis of severe pneumonia. Metabolomic analysis further validates THP's restorative effects on plasma metabolites, indicating its involvement in regulating energy metabolism and immune homeostasis. Mechanistically, THP targets the TLR4/NF-κB signaling pathway, a core mediator of inflammation, thereby dampening the inflammatory cascade. In summary, our findings underscore that THP, through its multifaceted actions targeting inflammation, oxidative stress, immune thrombus formation, gut microbiota regulation, and metabolic modulation, emerges as a promising therapeutic approach for severe pneumonia. This study provides invaluable insights into the potential applications of natural polysaccharides in treating severe pneumonia and highlights the significance of the TLR4/NF-κB pathway in the disease's progression.
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Affiliation(s)
- Fangmei Zhou
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Ying Guo
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Wenxuan Li
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Yiwen Hu
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Liu Yang
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Siyu Fu
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Xiaodan Bao
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Hongbin Tong
- Hangzhou HealthBank Medical Laboratory Co., Ltd., Hangzhou, Zhejiang 310053, China
| | - Yujian Ye
- Department of Dermatology, Third People's Hospital of Hangzhou, Hangzhou, China.
| | - Zhishan Ding
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
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Adamescu AI, Tilișcan C, Stratan LM, Mihai N, Ganea OA, Ciobanu S, Marinescu AG, Aramă V, Aramă ȘS. Decoding Inflammation: The Role of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Predicting Critical Outcomes in COVID-19 Patients. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:634. [PMID: 40282925 PMCID: PMC12028830 DOI: 10.3390/medicina61040634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 03/27/2025] [Accepted: 03/29/2025] [Indexed: 04/29/2025]
Abstract
Background and Objectives: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are novel biomarkers that provide insight into systemic inflammation and how the immune system responds to stress or infection. These ratios have been associated with predicting clinical outcomes in various diseases, including COVID-19. This study aims to evaluate the prognostic value of NLR and PLR in anticipating ICU admission, acute respiratory failure, and disease severity in COVID-19 patients. Materials and Methods: We conducted a retrospective, observational study that included 536 patients diagnosed with COVID-19. We analyzed the NLR and PLR values at admission and correlated them with ICU admission, the onset of acute respiratory failure, and clinical outcomes. Results: Statistical correlations were identified between elevated NLR and PLR values and the development of complications during hospitalization (p = 0.04 and p = 0.00), acute hypoxemic respiratory failure (p = 0.00), and admission to the intensive care unit (ICU) (p = 0.04). No correlations were found between the values of these ratios and mortality (p = 0.46 and p = 0.32) nor with the development of hepatic cytolysis (p = 0.79 and p = 0.87). Conclusions: NLR and PLR are reliable, easily obtainable biomarkers that can aid in the early prediction of ICU admission and disease severity in COVID-19 patients, offering valuable insights for risk stratification and clinical management. Further prospective studies are needed to validate these biomarkers as part of a broader predictive model for critical care in COVID-19.
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Affiliation(s)
- Aida-Isabela Adamescu
- Department II, Pathophysiology and Immunology, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.-I.A.)
- Prof. Dr. Matei Bals National Institute of Infectious Diseases, 021105 Bucharest, Romania
| | - Cătălin Tilișcan
- Department II, Pathophysiology and Immunology, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.-I.A.)
- Prof. Dr. Matei Bals National Institute of Infectious Diseases, 021105 Bucharest, Romania
| | - Laurențiu Mihăiță Stratan
- Prof. Dr. Matei Bals National Institute of Infectious Diseases, 021105 Bucharest, Romania
- Department II, Infectious Diseases, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Nicoleta Mihai
- Prof. Dr. Matei Bals National Institute of Infectious Diseases, 021105 Bucharest, Romania
- Department II, Infectious Diseases, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Oana-Alexandra Ganea
- Prof. Dr. Matei Bals National Institute of Infectious Diseases, 021105 Bucharest, Romania
- Department II, Infectious Diseases, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Sebastian Ciobanu
- Department II, Pathophysiology and Immunology, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.-I.A.)
- Emergency University Hospital, 050098 Bucharest, Romania
| | - Adrian Gabriel Marinescu
- Prof. Dr. Matei Bals National Institute of Infectious Diseases, 021105 Bucharest, Romania
- Department II, Infectious Diseases, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Victoria Aramă
- Prof. Dr. Matei Bals National Institute of Infectious Diseases, 021105 Bucharest, Romania
- Department II, Infectious Diseases, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Ștefan Sorin Aramă
- Department II, Pathophysiology and Immunology, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.-I.A.)
- Prof. Dr. Matei Bals National Institute of Infectious Diseases, 021105 Bucharest, Romania
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Yuan L, Stoddard M, Sarkar S, van Egeren D, Mangalaganesh S, Nolan RP, Rogers MS, Hather G, White LF, Chakravarty A. The Impact of Vaccination Frequency on COVID-19 Public Health Outcomes: A Model-Based Analysis. Vaccines (Basel) 2025; 13:368. [PMID: 40333247 PMCID: PMC12031506 DOI: 10.3390/vaccines13040368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 03/16/2025] [Accepted: 03/27/2025] [Indexed: 05/09/2025] Open
Abstract
Background: While the rapid deployment of SARS-CoV-2 vaccines had a significant impact on the ongoing COVID-19 pandemic, rapid viral immune evasion and waning neutralizing antibody titers have degraded vaccine efficacy. Nevertheless, vaccine manufacturers and public health authorities have a number of options at their disposal to maximize the benefits of vaccination. In particular, the effect of booster schedules on vaccine performance bears further study. Methods: To better understand the effect of booster schedules on vaccine performance, we used an agent-based modeling framework and a population pharmacokinetic model to simulate the impact of boosting frequency on the durability of vaccine protection against infection and severe acute disease. Results: Our work suggests that repeated dosing at frequent intervals (three or more times a year) may offset the degradation of vaccine efficacy, preserving the utility of vaccines in managing the ongoing pandemic. Conclusions: Given the practical significance of potential improvements in vaccine utility, clinical research to better understand the effects of repeated vaccination would be highly impactful. These findings are particularly relevant as public health authorities worldwide have reduced the frequency of boosters to once a year or less.
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Affiliation(s)
- Lin Yuan
- Fractal Therapeutics, Lexington, MA 02420, USA; (L.Y.); (M.S.)
| | | | - Sharanya Sarkar
- Department of Microbiology and Immunology, Dartmouth College, Hanover, NH 03755, USA;
| | - Debra van Egeren
- Department of Oncology, School of Medicine, Stanford University, Stanford, CA 94305, USA;
| | - Shruthi Mangalaganesh
- Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC 3800, Australia;
| | | | - Michael S. Rogers
- Department of Surgery, Harvard Medical School, Boston, MA 02114, USA;
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Greg Hather
- Sage Therapeutics, Cambridge, MA 02142, USA;
| | - Laura F. White
- School of Public Health, Boston University, Boston, MA 02118, USA;
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Sha J, Kong G, Fu L, Wang P, Zhang L, Wang T, Song F, Chu Y, Meng M. Impact of Early Administration of Albumin on Mortality Among Severe COVID-19 Patients, China. Infect Drug Resist 2025; 18:1539-1549. [PMID: 40123713 PMCID: PMC11930246 DOI: 10.2147/idr.s510245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 03/15/2025] [Indexed: 03/25/2025] Open
Abstract
Purpose Hypoalbuminemia is commonly observed in patients with severe Coronavirus Disease 2019 (COVID-19) and is independently associated with adverse outcomes. However, the efficacy of albumin administration on the clinical prognosis of these patients remains uncertain. Patients and Methods This multicenter retrospective study enrolled 458 patients with severe COVID-19 in four medical centers from December 1, 2022, to June 1, 2024. Clinical features and laboratory variables were collected through electronic medical records. The cohorts were divided into two groups: albumin administration and non-albumin administration. Propensity score matching (PSM) was used for minimizing confounding effect. Statistical analyses were conducted to assess the relationship between early albumin administration and 28-day mortality. Results Four hundred and fifty-eight severe COVID-19 cases were included in the study, of which 167 (36.5%) received early albumin administration, while 291 (63.5%) did not. Among these patients, 140 experienced in-hospital mortality and 318 survived. Compared to survivors, non-survivors exhibited significantly lower serum albumin levels (29.1g/L vs.33.8g/L, p < 0.05). In comparison to patients with admission albumin levels ≥30 g/L, those with albumin levels <30 g/L had a significantly higher in-hospital mortality (48.4% vs 21.1%, p < 0.001). Prior to PSM, the albumin administration group demonstrated significantly higher 28-day and in-hospital cumulative survival rates compared to the non-albumin group (both p < 0.001). However, no significant differences were observed between the two groups following PSM (p = 0.21 and p = 0.41, respectively). Conclusion Hypoalbuminemia was correlated with adverse outcomes in severe COVID-19 patients. However, early albumin administration did not reduce 28-day mortality and in-hospital mortality in these patients, and more relative RCTs were required for validation.
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Affiliation(s)
- Jing Sha
- Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, People’s Republic of China
| | - Guiqing Kong
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China
| | - Lin Fu
- Department of Critical Care Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China
| | - Peng Wang
- Neurocritical Care Unit, Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, Shandong, People’s Republic of China
| | - Lin Zhang
- Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, People’s Republic of China
| | - Tao Wang
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China
| | - Fangqiang Song
- Department of Critical Care Medicine, Tengzhou Central People’s Hospital, Tengzhou, Shandong, People’s Republic of China
| | - Yufeng Chu
- Neurocritical Care Unit, Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, Shandong, People’s Republic of China
| | - Mei Meng
- Department of Critical Care Medicine, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China
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Alrasheed AR, Awadalla M, Alnajran H, Alammash MH, Almaqati AM, Qadri I, Alosaimi B. Harnessing immunotherapeutic molecules and diagnostic biomarkers as human-derived adjuvants for MERS-CoV vaccine development. Front Immunol 2025; 16:1538301. [PMID: 40181980 PMCID: PMC11965926 DOI: 10.3389/fimmu.2025.1538301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 02/20/2025] [Indexed: 04/05/2025] Open
Abstract
The pandemic potential of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) highlights the critical need for effective vaccines due to its high fatality rate of around 36%. In this review, we identified a variety of immunotherapeutic molecules and diagnostic biomarkers that could be used in MERS vaccine development as human-derived adjuvants. We identified immune molecules that have been incorporated into standard clinical diagnostics such as CXCL10/IP10, CXCL8/IL-8, CCL5/RANTES, IL-6, and the complement proteins Ca3 and Ca5. Utilization of different human monoclonal antibodies in the treatment of MERS-CoV patients demonstrates promising outcomes in combatting MERS-CoV infections in vivo, such as hMS-1, 4C2H, 3B11-N, NBMS10-FC, HR2P-M2, SAB-301, M336, LCA60, REGN3051, REGN3048, MCA1, MERs-4, MERs-27, MERs-gd27, and MERs-gd33. Host-derived adjuvants such as CCL28, CCL27, RANTES, TCA3, and GM-CSF have shown significant improvements in immune responses, underscoring their potential to bolster both systemic and mucosal immunity. In conclusion, we believe that host-derived adjuvants like HBD-2, CD40L, and LL-37 offer significant advantages over synthetic options in vaccine development, underscoring the need for clinical trials to validate their efficacy.
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Affiliation(s)
- Abdullah R. Alrasheed
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Maaweya Awadalla
- Research Center, King Fahad Medical City, Riyadh Second Health Cluster, Riyadh, Saudi Arabia
| | - Hadeel Alnajran
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | | | - Adil M. Almaqati
- Riyadh Regional Laboratory, Ministry of Health, Riyadh, Saudi Arabia
| | - Ishtiaq Qadri
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Bandar Alosaimi
- Research Center, King Fahad Medical City, Riyadh Second Health Cluster, Riyadh, Saudi Arabia
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Hu Y, Lu Y, Dong J, Xia D, Li J, Wang H, Rao M, Wang C, Tong W. Epidemiological and clinical characteristics of COVID-19 mortality: a retrospective study. Front Med (Lausanne) 2025; 12:1464274. [PMID: 40130249 PMCID: PMC11930819 DOI: 10.3389/fmed.2025.1464274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 02/25/2025] [Indexed: 03/26/2025] Open
Abstract
Background The global impact of SARS-CoV-2 and its associated coronavirus disease (COVID-19) has necessitated urgent characterization of prognostic biomarkers. This study aimed to delineate the epidemiological and clinical predictors of mortality among hospitalized COVID-19 patients. Methods A retrospective cohort study was conducted on 123 patients with laboratory-confirmed COVID-19 admitted to Huoshenshan Hospital (Wuhan, China) from 1 February 2020 to 30 April 2020. Kaplan-Meier curve and multivariate Cox regression were used to assess the independent factors with survival time. Statistical significance was set at a p-value of <0.05. Results The cohort exhibited a mortality rate of 49.6% (61/123), with the critical clinical type (HR = 7.970, p = 0.009), leukocytosis (HR = 3.408, p = 0.006), and lymphopenia (HR = 0.817, p = 0.038) emerging as independent predictors of reduced survival. Critical-type patients demonstrated significantly elevated inflammatory markers (neutrophils: 10.41 ± 6.23 × 109/L; CRP: 104.47 ± 29.18 mg/L) and coagulopathy (D-dimer: 5.21 ± 2.34 μg/ml) compared to non-critical cases. Deceased patients exhibited pronounced metabolic derangements, including hyperglycemia (9.81 ± 2.07 mmol/L) and hepatic dysfunction (ALP: 174.03 ± 30.13 U/L). Conclusion We revealed the epidemiological and clinical features of different clinical types of SARS-CoV-2 as summarized in this paper. We found that critical type, leukocyte, and lymphocyte are risk factors that affect survival time, which could be an early and helpful marker to improve management of COVID-19 patients.
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Affiliation(s)
- Yaohua Hu
- Department of Respiratory and Critical Care Medicine, Naval Medical Center of People’s Liberation Army, Shanghai, China
| | - You Lu
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Shanghai, China
| | - Jiagui Dong
- Department of Respiratory and Critical Care Medicine, Naval Medical Center of People’s Liberation Army, Shanghai, China
| | - Delin Xia
- Department of Respiratory and Critical Care Medicine, Naval Medical Center of People’s Liberation Army, Shanghai, China
| | - Jin Li
- Department of Respiratory and Critical Care Medicine, Naval Medical Center of People’s Liberation Army, Shanghai, China
| | - Hong Wang
- Department of Respiratory and Critical Care Medicine, Naval Medical Center of People’s Liberation Army, Shanghai, China
| | - Min Rao
- Department of Respiratory and Critical Care Medicine, Naval Medical Center of People’s Liberation Army, Shanghai, China
| | - Chenxing Wang
- Department of Respiratory and Critical Care Medicine, Naval Medical Center of People’s Liberation Army, Shanghai, China
| | - Wanning Tong
- Department of Respiratory and Critical Care Medicine, Naval Medical Center of People’s Liberation Army, Shanghai, China
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de Oliveira JN, Fernandes CYM, de Godoy SM, Frantine-Silva W, de Souza Cassela PLC, Trigo GL, Lozovoy MAB, Tano ZN, Simão ANC, de Oliveira KB. Association of IL10 gene SNVs rs1800896 (A>G), rs1800871 (C>T), rs1800872 (C>A) and haplotypes with COVID-19 severity and outcome in the Brazilian population. Hum Immunol 2025; 86:111261. [PMID: 39933261 DOI: 10.1016/j.humimm.2025.111261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/13/2025]
Abstract
BACKGROUND Elevated concentrations of IL-10 have been detected in coronavirus disease (COVID-19) patients and are a possible disease severity marker. Single nucleotide variants (SNVs) and their haplotypes can be associated with differences in IL-10 levels and with viral disease susceptibility. AIM Evaluate the associations of SNVs and their haplotypes in Brazilian patients with COVID-19 severity and outcome. METHODS In this cross-sectional and case-control study, the patients were selected from the University Hospital of State University of Londrina (HU-UEL) (n = 367) and were subdivided into mild (n = 165), moderate (n = 72) and severe (n = 130) groups. The DNA samples of the participants were subjected to real-time PCR for the detection of rs1800896 (A>G), rs1800871 (C>T) and rs1800872 (C>A) genotypes. The haplotypes were inferred with PHASE v2.1.1. RESULTS The severe cases of COVID-19 were independently associated with the GG genotype (rs1800896) (P = 0.038, OR 2.522, 95 % CI 1.053-6.038) as well as with the GCC haplotype in homozygosity (P = 0.037, OR 2.767, 95 % CI 1.065-7.191). CONCLUSION These results showed that the GG genotype of rs1800896 or the GCC haplotype are associated with COVID-19 severity in Brazilian patients.
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Affiliation(s)
- Janaina Nicolau de Oliveira
- Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, Pr 445 km 380 Celso Garcia Cid Highway 86.057-970 PR, Brazil
| | - Caroline Yukari Motoori Fernandes
- Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, Pr 445 km 380 Celso Garcia Cid Highway 86.057-970 PR, Brazil
| | - Sara Mataroli de Godoy
- Laboratory for Studies and Analysis of Polymorphisms, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina 86.057-970 PR, Brazil
| | - Wilson Frantine-Silva
- Laboratory for Studies and Analysis of Polymorphisms, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina 86.057-970 PR, Brazil
| | | | - Guilherme Lerner Trigo
- Department of Applied Pathology, Clinical and Toxicological Analysis, State University of Londrina 86.057-970 PR, Brazil
| | | | - Zuleica Naomi Tano
- Department of Clinical Medicine, University of Londrina, Londrina, PR, Brazil
| | - Andrea Name Colado Simão
- Department of Applied Pathology, Clinical and Toxicological Analysis, State University of Londrina 86.057-970 PR, Brazil
| | - Karen Brajão de Oliveira
- Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, Pr 445 km 380 Celso Garcia Cid Highway 86.057-970 PR, Brazil; Laboratory for Studies and Analysis of Polymorphisms, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina 86.057-970 PR, Brazil.
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Eriksson EM, Mueller I. Increased fatty acid production and macrophage-driven inflammation as key drivers of severe respiratory disease. Immunol Cell Biol 2025; 103:224-227. [PMID: 40047400 DOI: 10.1111/imcb.12852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
In this article, we discuss a recent article by Jia et al., where high OLAH expression was detected in severe and fatal respiratory disease which was associated with a number of processes and responses. These include high abundance of oleic acid, excessive cytokine release, high viral titres and lipid droplets and increased presence of lung-associated innate cells.
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Affiliation(s)
- Emily M Eriksson
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia
| | - Ivo Mueller
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia
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Chakraborty C, Bhattacharya M, Das A, Saha A. Regulation of miRNA in Cytokine Storm (CS) of COVID-19 and Other Viral Infection: An Exhaustive Review. Rev Med Virol 2025; 35:e70026. [PMID: 40032584 DOI: 10.1002/rmv.70026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 01/29/2025] [Accepted: 02/18/2025] [Indexed: 03/05/2025]
Abstract
In the initial stage of the COVID-19 pandemic, high case fatality was noted. The case fatality during this was associated with the cytokine storm (CS) or cytokine storm syndrome (CSS). Sometimes, virus infections are due to the excessive secretion of pro-inflammatory cytokines, leading to cytokine storms, which might be directed to ARDS, multi-organ failure, and death. However, it was noted that several miRNAs are involved in regulating cytokines during SARS-CoV-2 and other viruses such as IFNs, ILs, GM-CSF, TNF, etc. The article spotlighted several miRNAs involved in regulating cytokines associated with the cytokine storm caused by SARS-CoV-2 and other viruses (influenza virus, MERS-CoV, SARS-CoV, dengue virus). Targeting those miRNAs might help in the discovery of novel therapeutics, considering CS or CSS associated with different virus infections.
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Affiliation(s)
- Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, India
| | | | - Arpita Das
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, India
| | - Abinit Saha
- Deparment of Zoology, J.K. College, Purulia, India
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Kaya H, Argun Baris S, Gultepe B, Basyigit I, Boyaci H. The predictive value of the LDH-albumin ratio on poor clinical course and mortality in COVID-19 patients: A single-center study. Medicine (Baltimore) 2025; 104:e41660. [PMID: 40020123 PMCID: PMC11875623 DOI: 10.1097/md.0000000000041660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 02/06/2025] [Indexed: 03/05/2025] Open
Abstract
There are studies evaluating the association of serum lactate dehydrogenase (LDH) and albumin levels with mortality in COVID-19 patients. The aim of our study was to evaluate the predictive effect of the LDH/albumin ratio (LAR) on mortality and poor clinical course in COVID-19 patients. A total of 2093 patients for whom LDH and albumin tests were available were included in the study. Demographic data, length of hospitalization, and signs of poor clinical course were recorded and compared with the LAR value at the time of hospitalization. The study included 1010 female (48.3%) and 1083 male (51.7%) patients. Notably, 1408 (67.3%) of the patients had at least 1 comorbidity. Oxygen was required in 860 patients (41.1%) and intensive care unit was required in 215 patients (10.3%). The mortality rate was 8.1% (n: 170). The median LAR value was 8.05. A positive correlation was observed between LAR and length of hospitalization. The LAR value was significantly higher in patients who died compared with those who survived, in patients who required intensive care compared with those who did not, and in patients who required oxygen compared to those who did not. The cutoff value for LAR in predicting mortality was calculated as 10.48. The sensitivity and specificity were determined as 73.5% and 73.7%. In conclusion, serum LAR at the time of admission is predictive of poor clinical course and mortality in COVID-19 patients. Patients with LAR values higher than the cutoff value should be closely monitored for poor clinical course.
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Affiliation(s)
- Huseyin Kaya
- Department of Chest Diseases, Kocaeli City Hospital, Izmit, Kocaeli, Turkey
| | - Serap Argun Baris
- Department of Chest Diseases, University of Kocaeli, Izmit, Kocaeli, Turkey
| | | | - Ilknur Basyigit
- Department of Chest Diseases, University of Kocaeli, Izmit, Kocaeli, Turkey
| | - Hasim Boyaci
- Department of Chest Diseases, University of Kocaeli, Izmit, Kocaeli, Turkey
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Fratta Pasini AM, Stranieri C, Di Leo EG, Bertolone L, Aparo A, Busti F, Castagna A, Vianello A, Chesini F, Friso S, Girelli D, Cominacini L. Identification of Early Biomarkers of Mortality in COVID-19 Hospitalized Patients: A LASSO-Based Cox and Logistic Approach. Viruses 2025; 17:359. [PMID: 40143288 PMCID: PMC11946718 DOI: 10.3390/v17030359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 02/06/2025] [Accepted: 02/20/2025] [Indexed: 03/28/2025] Open
Abstract
This study aimed to identify possible early biomarkers of mortality among clinical and biochemical parameters, iron metabolism parameters, and cytokines detected within 24 h from admission in hospitalized COVID-19 patients. We enrolled 80 hospitalized patients (40 survivors and 40 non-survivors) with COVID-19 pneumonia and acute respiratory failure. The median time from the onset of COVID-19 symptoms to hospital admission was lower in non-survivors than survivors (p < 0.05). Respiratory failure, expressed as the ratio of arterial oxygen partial pressure to the fraction of inspired oxygen (P/F), was more severe in non-survivors than survivors (p < 0.0001). Comorbidities were similar in both groups. Among biochemical parameters and cytokines, eGFR and interleukin (IL)-1β were found to be significantly lower (p < 0.05), while LDH, IL-10, and IL-8 were significantly higher in non-survivors than in survivors (p < 0.0005, p < 0.05 and p < 0.005, respectively). Among other parameters, LDH values distribution showed the most significant difference between study groups (p < 0.0001). LASSO feature selection combined with Cox proportional hazards and logistic regression models was applied to identify features distinguishing between survivors and non-survivors. Both approaches highlighted LDH as the strongest predictor, with IL-22 and creatinine emerging in the Cox model, while IL-10, eGFR, and creatinine were influential in the logistic model (AUC = 0.744 for Cox, 0.723 for logistic regression). In a similar manner, we applied linear regression for predicting LDH levels, identifying the P/F ratio as the top predictor, followed by IL-10 and eGFR (NRMSE = 0.128). Collectively, these findings underscore LDH's critical role in mortality prediction, with P/F and IL-10 as key determinants of LDH increases in this Italian COVID-19 cohort.
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Affiliation(s)
- Anna Maria Fratta Pasini
- Department of Medicine, Section of Internal Medicine D, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy; (C.S.); (E.G.D.L.); (L.B.); (F.B.); (A.V.); (F.C.); (D.G.); (L.C.)
| | - Chiara Stranieri
- Department of Medicine, Section of Internal Medicine D, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy; (C.S.); (E.G.D.L.); (L.B.); (F.B.); (A.V.); (F.C.); (D.G.); (L.C.)
| | - Edoardo Giuseppe Di Leo
- Department of Medicine, Section of Internal Medicine D, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy; (C.S.); (E.G.D.L.); (L.B.); (F.B.); (A.V.); (F.C.); (D.G.); (L.C.)
| | - Lorenzo Bertolone
- Department of Medicine, Section of Internal Medicine D, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy; (C.S.); (E.G.D.L.); (L.B.); (F.B.); (A.V.); (F.C.); (D.G.); (L.C.)
| | - Antonino Aparo
- Interdepartmental Laboratory of Medical Research, Research Center LURM, University of Verona, 37134 Verona, Italy;
| | - Fabiana Busti
- Department of Medicine, Section of Internal Medicine D, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy; (C.S.); (E.G.D.L.); (L.B.); (F.B.); (A.V.); (F.C.); (D.G.); (L.C.)
| | - Annalisa Castagna
- Department of Medicine, Section of Internal Medicine B, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy (S.F.)
| | - Alice Vianello
- Department of Medicine, Section of Internal Medicine D, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy; (C.S.); (E.G.D.L.); (L.B.); (F.B.); (A.V.); (F.C.); (D.G.); (L.C.)
| | - Fabio Chesini
- Department of Medicine, Section of Internal Medicine D, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy; (C.S.); (E.G.D.L.); (L.B.); (F.B.); (A.V.); (F.C.); (D.G.); (L.C.)
| | - Simonetta Friso
- Department of Medicine, Section of Internal Medicine B, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy (S.F.)
| | - Domenico Girelli
- Department of Medicine, Section of Internal Medicine D, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy; (C.S.); (E.G.D.L.); (L.B.); (F.B.); (A.V.); (F.C.); (D.G.); (L.C.)
| | - Luciano Cominacini
- Department of Medicine, Section of Internal Medicine D, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy; (C.S.); (E.G.D.L.); (L.B.); (F.B.); (A.V.); (F.C.); (D.G.); (L.C.)
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Parlițeanu OA, Bălteanu MA, Zaharia DC, Constantinescu T, Cristea AM, Dumitrache-Rujinscki Ș, Nica AE, Voineag C, Alexe OS, Tabacu E, Croitoru A, Strâmbu I, Nemeș RM, Mahler B. The Impact of SARS-CoV-2 Infection on Glucose Homeostasis in Hospitalized Patients with Pulmonary Impairment. Diagnostics (Basel) 2025; 15:554. [PMID: 40075801 PMCID: PMC11898410 DOI: 10.3390/diagnostics15050554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 01/22/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Background and Objectives: We conducted a retrospective observational study to evaluate the impact of elevated blood glucose levels in patients with SARS-CoV-2 infection and a prior diagnosis of diabetes mellitus (DM) or newly diagnosed hyperglycemia. Materials and Methods: This study analyzed 6065 patients admitted to the COVID-19 departments of the "Marius Nasta" National Institute of Pulmonology in Bucharest, Romania, between 26 October 2020 and 5 January 2023. Of these, 813 patients (13.40%) were selected for analysis due to either a pre-existing diagnosis of DM or hyperglycemia at the time of hospital admission. Results: The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were elevated in patients with blood glucose levels exceeding 300 mg/dL. These elevations correlated with the presence of respiratory failure and increased mortality rates. Additionally, oxygen requirements were significantly higher at elevated blood glucose levels (p < 0.001), with a direct relationship between glycemia and oxygen demand. This was accompanied by lower oxygen saturation levels (p < 0.001). Maximum blood glucose levels were associated with the severity of respiratory failure (AUC 0.6, 95% CI: 0.56-0.63, p < 0.001). We identified cut-off values for blood glucose at admission (217.5 mg/dL) and maximum blood glucose during hospitalization (257.5 mg/dL), both of which were associated with disease severity and identified as risk factors for increased mortality. Conclusions: High blood glucose levels, both at admission and during hospitalization, were identified as risk factors for poor prognosis and increased mortality in patients with SARS-CoV-2 infection, regardless of whether the hyperglycemia was due to a prior diagnosis of DM or was newly developed during the hospital stay. These findings underscore the importance of glycemic control in the management of hospitalized COVID-19 patients.
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Affiliation(s)
- Oana-Andreea Parlițeanu
- Institutul Național de Pneumoftizologie Marius Nasta, 050159 București, Romania; (O.-A.P.); (D.C.Z.); (T.C.); (A.M.C.); (Ș.D.-R.); (E.T.); (A.C.); (I.S.); (R.M.N.); (B.M.)
| | - Mara-Amalia Bălteanu
- Institutul Național de Pneumoftizologie Marius Nasta, 050159 București, Romania; (O.-A.P.); (D.C.Z.); (T.C.); (A.M.C.); (Ș.D.-R.); (E.T.); (A.C.); (I.S.); (R.M.N.); (B.M.)
| | - Dragoș Cosmin Zaharia
- Institutul Național de Pneumoftizologie Marius Nasta, 050159 București, Romania; (O.-A.P.); (D.C.Z.); (T.C.); (A.M.C.); (Ș.D.-R.); (E.T.); (A.C.); (I.S.); (R.M.N.); (B.M.)
- Department of Pneumology, Universitatea de Medicină și Farmacie Carol Davila, 050474 Bucrești, Romania;
| | - Tudor Constantinescu
- Institutul Național de Pneumoftizologie Marius Nasta, 050159 București, Romania; (O.-A.P.); (D.C.Z.); (T.C.); (A.M.C.); (Ș.D.-R.); (E.T.); (A.C.); (I.S.); (R.M.N.); (B.M.)
- Department of Pneumology, Universitatea de Medicină și Farmacie Carol Davila, 050474 Bucrești, Romania;
| | - Alexandra Maria Cristea
- Institutul Național de Pneumoftizologie Marius Nasta, 050159 București, Romania; (O.-A.P.); (D.C.Z.); (T.C.); (A.M.C.); (Ș.D.-R.); (E.T.); (A.C.); (I.S.); (R.M.N.); (B.M.)
- Department of Pneumology, Universitatea de Medicină și Farmacie Carol Davila, 050474 Bucrești, Romania;
| | - Ștefan Dumitrache-Rujinscki
- Institutul Național de Pneumoftizologie Marius Nasta, 050159 București, Romania; (O.-A.P.); (D.C.Z.); (T.C.); (A.M.C.); (Ș.D.-R.); (E.T.); (A.C.); (I.S.); (R.M.N.); (B.M.)
- Department of Pneumology, Universitatea de Medicină și Farmacie Carol Davila, 050474 Bucrești, Romania;
| | - Andra Elena Nica
- Department of Pneumology, Universitatea de Medicină și Farmacie Carol Davila, 050474 Bucrești, Romania;
| | - Cristiana Voineag
- Department of Diabetes, Universitatea Dunărea de Jos, 800201 Galați, Romania; (C.V.); (O.S.A.)
| | - Octavian Sabin Alexe
- Department of Diabetes, Universitatea Dunărea de Jos, 800201 Galați, Romania; (C.V.); (O.S.A.)
| | - Emilia Tabacu
- Institutul Național de Pneumoftizologie Marius Nasta, 050159 București, Romania; (O.-A.P.); (D.C.Z.); (T.C.); (A.M.C.); (Ș.D.-R.); (E.T.); (A.C.); (I.S.); (R.M.N.); (B.M.)
- Department of Pneumology, Universitatea de Medicină și Farmacie Carol Davila, 050474 Bucrești, Romania;
| | - Alina Croitoru
- Institutul Național de Pneumoftizologie Marius Nasta, 050159 București, Romania; (O.-A.P.); (D.C.Z.); (T.C.); (A.M.C.); (Ș.D.-R.); (E.T.); (A.C.); (I.S.); (R.M.N.); (B.M.)
- Department of Pneumology, Universitatea de Medicină și Farmacie Carol Davila, 050474 Bucrești, Romania;
| | - Irina Strâmbu
- Institutul Național de Pneumoftizologie Marius Nasta, 050159 București, Romania; (O.-A.P.); (D.C.Z.); (T.C.); (A.M.C.); (Ș.D.-R.); (E.T.); (A.C.); (I.S.); (R.M.N.); (B.M.)
- Department of Pneumology, Universitatea de Medicină și Farmacie Carol Davila, 050474 Bucrești, Romania;
| | - Roxana Maria Nemeș
- Institutul Național de Pneumoftizologie Marius Nasta, 050159 București, Romania; (O.-A.P.); (D.C.Z.); (T.C.); (A.M.C.); (Ș.D.-R.); (E.T.); (A.C.); (I.S.); (R.M.N.); (B.M.)
| | - Beatrice Mahler
- Institutul Național de Pneumoftizologie Marius Nasta, 050159 București, Romania; (O.-A.P.); (D.C.Z.); (T.C.); (A.M.C.); (Ș.D.-R.); (E.T.); (A.C.); (I.S.); (R.M.N.); (B.M.)
- Department of Pneumology, Universitatea de Medicină și Farmacie Carol Davila, 050474 Bucrești, Romania;
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Casetti R, Sacchi A, Mazzotta V, Cristofanelli F, Grassi G, Gili S, Cimini E, Notari S, Bordoni V, Mastrorosa I, Giancola ML, Vergori A, Tempestilli M, Vita S, Mariotti D, Rosati S, Lalle E, Meschi S, Colavita F, Garbuglia AR, Girardi E, Nicastri E, Antinori A, Agrati C. Innate and SARS-CoV-2 specific adaptive immune response kinetic in neutralizing monoclonal antibody successfully treated COVID-19 patients. Int Immunopharmacol 2025; 148:113934. [PMID: 39832460 DOI: 10.1016/j.intimp.2024.113934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 12/06/2024] [Accepted: 12/21/2024] [Indexed: 01/22/2025]
Abstract
The impact of anti-Spike monoclonal antibody (mAbs) treatment on the immune response of COVID19-patients is poorly explored. In particular, a comparison of the immunological influence of different therapeutic regimens has not yet been performed. Aim of the study was to compare the kinetic of innate and adaptive immune response as well as the SARS-CoV-2 specific humoral and T cell response in two groups of SARS-CoV-2-infected patients treated with two different mAbs regimens: Bamlanivimab/Etesevimab (BAM/ETE) or Casirivimab/Imdevimab (CAS/IMD). SARS-CoV-2-infected patients (n = 39) with mild/moderate disease were enrolled before (T0) and after 7 days (T7) and 30 day (T30) from mAbs infusion. Patients were divided in two groups on the basis of the mAb regimen: BAM/ETE (n = 15) and CAS/IMD (n = 24). The phenotype/function of immune cell subsets was evaluated by flow-cytometry and by ELISA. The Spike-specific T cell response (IFN-γ) and anti-Nucleocapside IgG were evaluated by chemiluminescence assay. SARS CoV-2 RNA in nasal swabs was evaluated by RT-PCR. Eleven out of the thirty-nine enrolled patients tested negative at T7, among which nine (81.8 %) had been treated with CAS/IMD regimen. A comparable increase in CD4 and CD8 T cells was observed in both treatment groups. Moreover, a reduction of CD38 expression on T (CD4, CD8 and Vδ2) and on NK cells was observed in both groups, as well as a reduction overtime of the perforin expression in T (CD8, Vδ2) and in NK cells reaching significance only in CAS/IMD-treated patients. The SARS-CoV-2-specific T cells response increased at T7 in BAM/ETE-treated patients and at T30 in CAS/IND group. Of note, at T30 SARS-CoV2-specific T cells was higher in CAS/IMD than in BAM/ETE group. Furthermore, the titre of anti-N IgG increased overtime in both groups with a faster kinetic in CAS/IMD group. The spontaneous production of inflammatory cytokines by monocytes and neutrophils was similar the two mAb regimens, as well as the level of plasmatic IL-6. Finally, patients were also analysed according to sex. The male group showed a higher frequency of activated CD4 T cells, NKG2A-expressing CD8 T cells and perforin-expressing Vδ2 T cells compared to female group. Moreover, a higher specific T cell response at T30 was observed in the male compared to female group. In conclusion, these results show similar effects of both mAb regimens in restoring T and NK cell homeostasis and in reducing inflammation. In contrast, CAS/IMD allows a better humoral and cellular SARS-CoV2 specific immunization.
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Affiliation(s)
- Rita Casetti
- Cellular Immunology and Pharmacology Laboratory, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Alessandra Sacchi
- Molecular Virology and Antimicrobic Immunity Laboratory, Department of Science, University of Rome Three, 00146 Rome, Italy.
| | | | - Flavia Cristofanelli
- Cellular Immunology and Pharmacology Laboratory, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Germana Grassi
- Cellular Immunology and Pharmacology Laboratory, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Simona Gili
- Cellular Immunology and Pharmacology Laboratory, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Eleonora Cimini
- Cellular Immunology and Pharmacology Laboratory, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Stefania Notari
- Cellular Immunology and Pharmacology Laboratory, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Veronica Bordoni
- Unit of Pathogen Specific Immunity, Bambino Gesù Children's Hospital, IRCCS, Rome 00146 Italy.
| | | | | | | | - Massimo Tempestilli
- Cellular Immunology and Pharmacology Laboratory, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Serena Vita
- Clinical Department, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Davide Mariotti
- Virology Laboratory, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Silvia Rosati
- Clinical Department, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Eleonora Lalle
- Virology Laboratory, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Silvia Meschi
- Virology Laboratory, INMI L. Spallanzani, 00149 Rome, Italy.
| | | | | | - Enrico Girardi
- Scientific Directorate, INMI L. Spallanzani, 00149 Rome, Italy.
| | | | - Andrea Antinori
- Clinical Department, INMI L. Spallanzani, 00149 Rome, Italy.
| | - Chiara Agrati
- Unit of Pathogen Specific Immunity, Bambino Gesù Children's Hospital, IRCCS, Rome 00146 Italy.
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Lee C, Khan R, Mantsounga CS, Sharma S, Pierce J, Amelotte E, Butler CA, Farinha A, Parry C, Caballero O, Morrison JA, Uppuluri S, Whyte JJ, Kennedy JL, Zhang X, Choudhary G, Olson RM, Morrison AR. IL-1β-driven NF-κB transcription of ACE2 as a Mechanism of Macrophage Infection by SARS-CoV-2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.12.24.630260. [PMID: 39763770 PMCID: PMC11703209 DOI: 10.1101/2024.12.24.630260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Coronavirus disease 2019 (COVID-19), caused by infection with the enveloped RNA betacoronavirus, SARS-CoV-2, led to a global pandemic involving over 7 million deaths. Macrophage inflammatory responses impact COVID-19 severity; however, it is unclear whether macrophages are infected by SARS-CoV-2. We sought to identify mechanisms regulating macrophage expression of ACE2, the primary receptor for SARS-CoV-2, and to determine if macrophages are susceptible to productive infection. We developed a humanized ACE2 (hACE2) mouse whereby hACE2 cDNA was cloned into the mouse ACE2 locus under control of the native promoter. We validated the susceptibility of hACE2 mice to SARS-CoV-2 infection relative to wild-type mice and an established K18-hACE2 model of acute fulminating disease. Intranasal exposure to SARS-CoV-2 led to pulmonary consolidations with cellular infiltrate, edema, and hemorrhage, consistent with pneumonia, yet unlike the K18-hACE2 model, hACE2 mice survived and maintained stable weight. Infected hACE2 mice also exhibited a unique plasma chemokine, cytokine, and growth factor inflammatory signature relative to K18-hACE2 mice. Infected hACE2 mice demonstrated evidence of viral replication in infiltrating lung macrophages, and infection of macrophages in vitro revealed a transcriptional profile indicative of altered RNA and ribosomal processing machinery as well as activated cellular antiviral defense. Macrophage IL-1β-driven NF-κB transcription of ACE2 was an important mechanism of dynamic ACE2 upregulation, promoting macrophage susceptibility to infection. Experimental models of COVID-19 that make use of native hACE2 expression will allow for mechanistic insight into factors that can either promote host resilience or increase susceptibility to worsening severity of infection.
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Affiliation(s)
- Cadence Lee
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Rachel Khan
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Chris S. Mantsounga
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Sheila Sharma
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Julia Pierce
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Elizabeth Amelotte
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Celia A. Butler
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Andrew Farinha
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Crystal Parry
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Olivya Caballero
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Jeremi A. Morrison
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Saketh Uppuluri
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Jeffrey J. Whyte
- Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, Missouri, USA
- Laboratory for Infectious Disease Research, University of Missouri Division of Research, Innovation and Impact, Columbia, Missouri, USA
| | - Joshua L. Kennedy
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
- Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
- Arkansas Children’s Research Institute, Little Rock, Arkansas, USA
| | - Xuming Zhang
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Gaurav Choudhary
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
- Cardiovascular Research Center, Lifespan Cardiovascular Research Institute, Rhode Island Hospital, Providence, Rhode Island, USA
| | - Rachel M. Olson
- Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, Missouri, USA
- Laboratory for Infectious Disease Research, University of Missouri Division of Research, Innovation and Impact, Columbia, Missouri, USA
| | - Alan R. Morrison
- Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island 02908, USA
- Ocean State Research Institute, Inc., Providence, Rhode Island 02908, USA
- Department of Internal Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
- Lead contact and corresponding author
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Adamopoulos PG, Bartzoka N, Tsiakanikas P, Scorilas A. Characterization of novel ACE2 mRNA transcripts: The potential role of alternative splicing in SARS-CoV-2 infection. Gene 2025; 936:149092. [PMID: 39549777 DOI: 10.1016/j.gene.2024.149092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 10/25/2024] [Accepted: 11/11/2024] [Indexed: 11/18/2024]
Abstract
The human angiotensin converting enzyme 2 (ACE2) gene encodes a type I transmembrane protein, which is homologous to angiotensin I-converting enzyme (ACE) and belongs to the angiotensin-converting enzyme family of dipeptidyl carboxypeptidases. As highlighted by the COVID-19 pandemic, ACE2 is not only crucial for the renin-angiotensin-aldosterone system (RAAS), but also displays great affinity with the SARS-CoV-2 spike protein, representing the major receptor of the virus. Given the significance of ACE2 in COVID-19, especially among cancer patients, the present study aims to explore the transcriptional landscape of ACE2 in human cancer and non-cancerous cell lines through the design and implementation of a custom targeted long-read sequencing approach. Bioinformatics analysis of the massive parallel sequencing data led to the identification of novel ACE2 mRNA splice variants (ACE2 sv.7-sv.12) that demonstrate previously uncharacterized exon-skipping events as well as 5' and/or 3' alternative splice sites. Demultiplexing of the sequencing data elucidated the differential expression profile of the identified splice variants in multiple human cell types, whereas in silico analysis suggests that some of the novel splice variants could produce truncated ACE2 isoforms with altered functionalities, potentially influencing their interaction with the SARS-CoV-2 spike protein. In summary, our study sheds light on the complex alternative splicing landscape of the ACE2 gene in cancer cell lines, revealing novel splice variants that could have significant implications for SARS-CoV-2 susceptibility in cancer patients. These findings contribute to the increased understanding of ACE2's role in COVID-19 and highlight the importance of considering alternative splicing as a key factor in viral pathogenesis. Undoubtably, further research is needed to explore the functional roles of these variants and their potential as therapeutic targets in the ongoing fight against COVID-19.
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Affiliation(s)
- Panagiotis G Adamopoulos
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Natalia Bartzoka
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Tsiakanikas
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece.
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Zhao Y, Tang Y, Wang QY, Li J. Ocular neuroinflammatory response secondary to SARS-CoV-2 infection-a review. Front Immunol 2025; 16:1515768. [PMID: 39967658 PMCID: PMC11832381 DOI: 10.3389/fimmu.2025.1515768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/13/2025] [Indexed: 02/20/2025] Open
Abstract
With the consistent occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the prevalence of various ocular complications has increased over time. SARS-CoV-2 infection has been shown to have neurotropism and therefore to lead to not only peripheral inflammatory responses but also neuroinflammation. Because the receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), can be found in many intraocular tissues, coronavirus disease 2019 (COVID-19) may also contribute to persistent intraocular neuroinflammation, microcirculation dysfunction and ocular symptoms. Increased awareness of neuroinflammation and future research on interventional strategies for SARS-CoV-2 infection are important for improving long-term outcomes, reducing disease burden, and improving quality of life. Therefore, the aim of this review is to focus on SARS-CoV-2 infection and intraocular neuroinflammation and to discuss current evidence and future perspectives, especially possible connections between conditions and potential treatment strategies.
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Affiliation(s)
| | | | | | - Jia Li
- Department of Glaucoma, The Second Hospital of Jilin University, Changchun, China
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Subramaniam S, Jose A, Kenney D, O’Connell AK, Bosmann M, Douam F, Crossland N. Challenging the notion of endothelial infection by SARS-CoV-2: insights from the current scientific evidence. Front Immunol 2025; 16:1443932. [PMID: 39967675 PMCID: PMC11832389 DOI: 10.3389/fimmu.2025.1443932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 01/14/2025] [Indexed: 02/20/2025] Open
Affiliation(s)
- Saravanan Subramaniam
- Department of Pharmacology and Toxicology, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, United States
- Renal Section, Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
| | - Asha Jose
- Renal Section, Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
| | - Devin Kenney
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
| | - Aoife K. O’Connell
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
| | - Markus Bosmann
- Department of Medicine, Pulmonary Center, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
- Department of Pathology and Laboratory Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
| | - Florian Douam
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
| | - Nicholas Crossland
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
- Department of Pathology and Laboratory Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
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47
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Lespezeanu DA, Kraft A, Moldovan C, Ungureanu D, Bacalbasa N. The short-term follow-up of patients with diabetes mellitus presenting with COVID-19. J Med Life 2025; 18:116-124. [PMID: 40134446 PMCID: PMC11932506 DOI: 10.25122/jml-2025-0027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 02/23/2025] [Indexed: 03/27/2025] Open
Abstract
The COVID-19 pandemic has disproportionately affected individuals with diabetes mellitus (DM), significantly increasing their risk of adverse outcomes. This retrospective study aimed to explore the underlying factors contributing to the heightened vulnerability of individuals with DM to severe COVID-19. We reviewed medical records of patients diagnosed with DM from August 2020 to August 2022 and identified 60 equally divided into two groups. Group A (n = 30) included those diagnosed with an associated COVID-19 infection, while Group B (n = 30) served as the control group without a COVID-19 infection. Inflammatory biomarkers, venous blood glucose levels, and other parameters were assessed at hospital admission and again after a 14-day treatment period. Statistical analysis confirmed a strong association between diabetes and COVID-19 infection. In COVID-19 patients treated with Empagliflozin, correlations were observed between IL-1, TNF-alpha, IL-6, and blood glucose levels. Patients in Group B did not show significant improvements in inflammatory markers or blood glucose control. In contrast, in the first group, better correlations between interleukin levels and blood glucose were demonstrated, suggesting a higher success rate for that treatment. Our findings indicate that while Empagliflozin had limited efficacy in managing long-term diabetes-related complications, it might offer significant benefits in the acute phase of illness.
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Affiliation(s)
- Delia-Andreea Lespezeanu
- Ion Pavel Diabetes Center, Prof. Dr. N. C. Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania
- Doctoral School, Titu Maiorescu University of Bucharest, Romania
| | - Alin Kraft
- Department of General Surgery, Regina Maria Military Emergency Hospital, Brasov, Romania
| | - Cosmin Moldovan
- Department of Medical-Surgical and Prophylactic Disciplines, Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania
- Department of General Surgery, Witting Clinical Hospital, Bucharest, Romania
| | - Dan Ungureanu
- Doctoral School, Titu Maiorescu University of Bucharest, Romania
| | - Nicolae Bacalbasa
- Department of Surgery, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Department of Visceral Surgery, Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- Department of Visceral Surgery, Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
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48
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García AMG, Arias Arias AJ, Muñoz FL, García-Rico E. Allostatic Load as a Short-Term Prognostic and Predictive Marker. Stress Health 2025; 41:e3527. [PMID: 39789760 DOI: 10.1002/smi.3527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/22/2024] [Accepted: 12/23/2024] [Indexed: 01/12/2025]
Abstract
It would be highly valuable to possess a tool for evaluating disease progression and identifying patients at risk of experiencing a more severe clinical course and potentially worse outcomes. The concept of allostatic load, which represents the overall strain on the body from repeated stress responses, has been recognized as a precursor to the development of chronic illnesses. It functions as a cumulative measure of the body's capacity to adapt to stress. Numerous studies have demonstrated that elevated allostatic load levels are associated with various negative health outcomes, both physical and mental, and are more predictive of mortality than individual biomarkers. Leveraging the unique circumstances presented by the COVID-19 pandemic, we evaluated different clinical and laboratory parameters in hospitalised COVID-19 patients to assess allostatic load. Our results indicated that allostatic load acts as a strong predictor of prolonged hospitalisation, increased ICU days, and mortality. This highlights its efficacy as a precise gauge of biological dysregulation linked to the response to COVID-19 during disease progression. Allostatic load is easily obtainable and provides an early, cost-effective indication of disease prognosis. Additionally, it has the potential to forecast the necessity for ICU admission. As a result, this parameter, indicative of the comprehensive physiological disruption in response to stress, emerges as a promising prognostic marker for hospitalised patients, extending beyond COVID-19.
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Affiliation(s)
- Ana M Gómez García
- Internal Medicine Unit, Hospital Universitario HM Madrid, Madrid, Spain
- Facultad HM de Ciencias de la Salud de la Universidad Camilo José Cela, Villafranca del Castillo, Spain
- Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain
| | - Angel Jesús Arias Arias
- Facultad HM de Ciencias de la Salud de la Universidad Camilo José Cela, Villafranca del Castillo, Spain
| | - Francisco López Muñoz
- Facultad HM de Ciencias de la Salud de la Universidad Camilo José Cela, Villafranca del Castillo, Spain
- Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain
| | - E García-Rico
- Facultad HM de Ciencias de la Salud de la Universidad Camilo José Cela, Villafranca del Castillo, Spain
- Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain
- Medical Oncology Unit, Hospital Universitario HM Torrelodones, Madrid, Spain
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Sobh A, Elnagdy MH, Mosa DM, Korkor MS, Alawfi AD, Alshengeti AM, Al-Mazroea AH, Bafail R, Samman WA, El-Agamy DS, Abo-Haded HM. Longitudinal cytokine profile in severe COVID-19 and multisystem inflammatory syndrome in children: A single centre study from Egypt. J Paediatr Child Health 2025; 61:249-261. [PMID: 39679634 DOI: 10.1111/jpc.16746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 10/22/2024] [Accepted: 11/28/2024] [Indexed: 12/17/2024]
Abstract
AIM The severity of COVID-19 is influenced by uncontrolled hyper-inflammatory response with excessive release of many cytokines and chemokines. The understanding of the temporal change in the cytokine levels that underlies the diverse clinical presentations of COVID-19 can help in the prediction of the disease outcome and in the design of proper treatment strategies. METHOD Data were collected from children (<18 years old) hospitalised with severe COVID-19 or severe MIS-C who were compared to a group of healthy control children. Patient demographics, clinical, laboratory data and cytokines profiles were evaluated. Blood samples were collected within 24 h of admission for all enrolled children and on Day 14. RESULTS Twenty-five children with severe COVID-19 and 23 cases with severe MIS-C were included in the study. The biochemical and inflammatory markers tend to be elevated in MIS-C group. There was a significant difference between studied cases and the control group in the following cytokines: G-CSF, IL-10, HMGB1, TNF-α, IL-6, IL-8 and INF-gamma (P < 0.05). While there was a significant difference between severe COVID-19 and MIS-C groups in the following cytokines at Day 1 of admission; IL-10, IL-6, IL-8 and INF-gamma; while at Day 14, there was a significant difference only for G-CSF, IL-10 and IL-6, all other cytokines were comparable. CONCLUSION Our study underpinned patterns of cytokine response in severe COVID-19 and MIS-C. There is a significant upregulation in pro-inflammatory cytokines (mainly G-CSF, IL-10, HMGB1, TNF-α, IL-6, IL-8 and INF-gamma). These biomarkers that could imply on the severity rating and treatment strategies, should be preferentially assessed in SARS-CoV-2 associated immunological events.
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Affiliation(s)
- Ali Sobh
- Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Marwa H Elnagdy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Doaa Mosad Mosa
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mai S Korkor
- Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Abdulsalam D Alawfi
- Department of Pediatrics, College of Medicine, Taibah University, Madinah, Saudi Arabia
| | - Amer M Alshengeti
- Department of Pediatrics, College of Medicine, Taibah University, Madinah, Saudi Arabia
| | | | - Rawan Bafail
- Department of Pharmaceutics & Pharmaceutical Technology, College of Pharmacy, Taibah University, Madinah, Saudi Arabia
| | - Waad A Samman
- Department of Pharmacology & Toxicology, College of Pharmacy, Taibah University, Madinah, Saudi Arabia
| | - Dina S El-Agamy
- Department of Pharmacology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Hany M Abo-Haded
- Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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50
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Alirezaee A, Mirmoghtadaei M, Heydarlou H, Akbarian A, Alizadeh Z. Interferon therapy in alpha and Delta variants of SARS-CoV-2: The dichotomy between laboratory success and clinical realities. Cytokine 2025; 186:156829. [PMID: 39693873 DOI: 10.1016/j.cyto.2024.156829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 11/28/2024] [Accepted: 12/03/2024] [Indexed: 12/20/2024]
Abstract
The COVID-19 pandemic has caused significant morbidity and mortality worldwide. The emergence of the Alpha and Delta variants of SARS-CoV-2 has led to a renewed interest in using interferon therapy as a potential treatment option. Interferons are a group of signaling proteins produced by host cells in response to viral infections. They play a critical role in the innate immune response to viral infections by inducing an antiviral state in infected and neighboring cells. Interferon therapy has shown promise as a potential treatment option for COVID-19. In this review paper, we review the current knowledge regarding interferon therapy in the context of the Alpha and Delta variants of SARS-CoV-2 and discuss the challenges that must be overcome to translate laboratory findings into effective clinical treatments.
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Affiliation(s)
- Atefe Alirezaee
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran; Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Milad Mirmoghtadaei
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran; Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanieh Heydarlou
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran; Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Asiye Akbarian
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zahra Alizadeh
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran; Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.
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