|
1
|
Tremoulis DC, Papadopoulou G, Pogka V, Argyraki A, Lourida G, Mentis A, Karamitros T. Blood Transcriptome Profiling Highlights the Role of Intestinal Bacterial Translocation in Severe COVID-19. Pathogens 2025; 14:381. [PMID: 40333157 PMCID: PMC12030260 DOI: 10.3390/pathogens14040381] [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: 03/12/2025] [Revised: 04/10/2025] [Accepted: 04/11/2025] [Indexed: 05/09/2025] Open
Abstract
COVID-19 has caused millions of deaths globally; however, the characterization of molecular biomarkers of severe disease remains of great scientific importance. The aim of this study was to capture the transcriptional differences of the whole blood gene expression between COVID-19 patients with mild and severe disease, using Next Generation Sequencing technologies, on admission and after 7 days. The genes which were differentially expressed in severe compared to mild patients were used for Gene Ontology (GO) enrichment analysis. Gene expression data were used to estimate the cell abundance of 22 immune cell types via digital cytometry. GO terms related to the response to molecules of bacterial origin, such as intestine-derived lipopolysaccharide (LPS), were enriched, among other dysregulated pathways, which are well described as paramount mechanisms of severe manifestations of COVID-19. The neutrophil population increased in patients with severe disease, whereas the monocyte, CD8+ T cell, and activated Natural Killer (NK) cell populations were depleted. These cell population dynamics are also indicative of severe COVID-19 and intestinal bacterial translocation. This study elucidates the molecular basis of severe COVID-19 and highlights intestinal bacterial translocation as a potential driver of severe disease.
Collapse
Affiliation(s)
- Dimitrios Christos Tremoulis
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, Vasilissis Sofias 127, 11521 Athens, Greece
| | - Gethsimani Papadopoulou
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, Vasilissis Sofias 127, 11521 Athens, Greece
| | - Vasiliki Pogka
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, Vasilissis Sofias 127, 11521 Athens, Greece
| | - Aikaterini Argyraki
- Infectious Diseases Clinic A, Sotiria Chest Diseases Hospital, Mesogion 152, 11527 Athens, Greece
| | - Giota Lourida
- Infectious Diseases Clinic A, Sotiria Chest Diseases Hospital, Mesogion 152, 11527 Athens, Greece
| | - Andreas Mentis
- Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, Vasilissis Sofias 127, 11521 Athens, Greece
| |
Collapse
|
|
2
|
Fountoulakis PN, Theofilis P, Vlachakis PK, Karakasis P, Pamporis K, Sagris M, Dimitroglou Y, Tsioufis P, Oikonomou E, Tsioufis K, Tousoulis D. Gut Microbiota in Heart Failure-The Role of Inflammation. Biomedicines 2025; 13:911. [PMID: 40299538 PMCID: PMC12024997 DOI: 10.3390/biomedicines13040911] [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: 01/26/2025] [Revised: 03/30/2025] [Accepted: 03/31/2025] [Indexed: 04/30/2025] Open
Abstract
Heart failure (HF) has become an immense health concern affecting almost 1-2% of the population globally. It is a complex syndrome characterized by activation of the sympathetic nervous system and the Renin-Angiotensin-Aldosterone (RAAS) axis as well as endothelial dysfunction, oxidative stress, and inflammation. The recent literature points towards the interaction between the intestinal flora and the heart, also called the gut-heart axis. The human gastrointestinal tract is naturally inhabited by various microbes, which are distinct for each patient, regulating the functions of many organs. Alterations of the gut microbiome, a process called dysbiosis, may result in systemic diseases and have been associated with heart failure through inflammatory and autoimmune mechanisms. The disorder of intestinal permeability favors the translocation of microbes and many metabolites capable of inducing inflammation, thus further contributing to the deterioration of normal cardiac function. Besides diet modifications and exercise training, many studies have revealed possible gut microbiota targeted treatments for managing heart failure. The aim of this review is to demonstrate the impact of the inflammatory environment induced by the gut microbiome and its metabolites on heart failure and the elucidation of these novel therapeutic approaches.
Collapse
Affiliation(s)
- Petros N. Fountoulakis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.N.F.); (P.T.); (P.K.V.); (K.P.); (M.S.); (Y.D.); (P.T.); (K.T.)
| | - Panagiotis Theofilis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.N.F.); (P.T.); (P.K.V.); (K.P.); (M.S.); (Y.D.); (P.T.); (K.T.)
| | - Panayotis K. Vlachakis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.N.F.); (P.T.); (P.K.V.); (K.P.); (M.S.); (Y.D.); (P.T.); (K.T.)
| | - Paschalis Karakasis
- 2nd Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece;
| | - Konstantinos Pamporis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.N.F.); (P.T.); (P.K.V.); (K.P.); (M.S.); (Y.D.); (P.T.); (K.T.)
| | - Marios Sagris
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.N.F.); (P.T.); (P.K.V.); (K.P.); (M.S.); (Y.D.); (P.T.); (K.T.)
| | - Yannis Dimitroglou
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.N.F.); (P.T.); (P.K.V.); (K.P.); (M.S.); (Y.D.); (P.T.); (K.T.)
| | - Panagiotis Tsioufis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.N.F.); (P.T.); (P.K.V.); (K.P.); (M.S.); (Y.D.); (P.T.); (K.T.)
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Tsioufis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.N.F.); (P.T.); (P.K.V.); (K.P.); (M.S.); (Y.D.); (P.T.); (K.T.)
| | - Dimitris Tousoulis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.N.F.); (P.T.); (P.K.V.); (K.P.); (M.S.); (Y.D.); (P.T.); (K.T.)
| |
Collapse
|
|
3
|
Pellicano C, Oliva A, Colalillo A, Luceri C, Gigante A, Mastroianni CM, Tornese D, Carnazzo V, Basile V, Rosato E, Basile U. Markers of Endotoxemia and Inflammation are Associated with Digital Ulcers in Systemic Sclerosis Patients. Immunol Invest 2025:1-14. [PMID: 40099380 DOI: 10.1080/08820139.2025.2478932] [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: 03/19/2025]
Abstract
BACKGROUND The aim of this study was to evaluate the possible role of lipopolysaccharide-binding protein (LBP) and interleukin 6 (IL-6) in the development of digital ulcers (DUs) in Systemic sclerosis (SSc). METHODS 60 SSc patients were enrolled and tested for serum levels of LBP and IL-6. The development of DUs was assessed in a 12-month follow-up period. RESULTS Median LBP and IL-6 were 107.445 ng/mL and 10.8 pg/mL whilst 33.3% patients had LBP ≥ 11995 ng/mL and 51.7% patients had IL-6 ≥ 12.5 pg/mL. DUs history were present in 41.7% SSc patients and at follow-up 23.3% patients developed new DUs. Baseline LBP (14105 ng/mL vs 10355 ng/mL, p < .001) and IL-6 (195 pg/mL vs 9.4 ng/mL, p < .001) were higher in SSc patients with new DUs. The ROC curves showed a good diagnostic accuracy for a cut-off of LBP ≥ 11995 ng/mL [AUC = 0.804 (95% CI = 0.656-0.951), p < .001] and for a cut-off of IL-6 ≥ 12.5 pg/mL [AUC = 0.897 (95% CI = 0.783-1.000), p < .001]. Free survival from new DUs was shorter in SSc patients with increased LBP (p < .001) or IL-6 (p = .003). CONCLUSIONS LPB or IL-6 could play a role in digital microvascular damage of SSc patients.
Collapse
Affiliation(s)
- Chiara Pellicano
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessandra Oliva
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Amalia Colalillo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Cristina Luceri
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Antonietta Gigante
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Daniela Tornese
- Dipartimento di Patologia Clinica, Ospedale Santa Maria Goretti, Latina, Italy
| | - Valeria Carnazzo
- Dipartimento di Patologia Clinica, Ospedale Santa Maria Goretti, Latina, Italy
| | - Valerio Basile
- Clinical Pathology Unit and Cancer Biobank, Department of Research and Advanced Technologies, I.R.C.C.S. Regina Elena National Cancer Institute, Rome, Italy
| | - Edoardo Rosato
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Umberto Basile
- Dipartimento di Patologia Clinica, Ospedale Santa Maria Goretti, Latina, Italy
| |
Collapse
|
|
4
|
Carnevale R, Nocella C, Marocco R, Zuccalà P, Carraro A, Picchio V, Oliva A, Cangemi R, Miele MC, De Angelis M, Cancelli F, Casciaro GE, Cristiano L, Pignatelli P, Frati G, Venditti M, Pugliese F, Mastroianni CM, Violi F, Ridola L, Del Borgo C, Palmerio S, Valenzi E, Carnevale R, Alvaro D, Lichtner M, Cardinale V. Association Between NOX2-Mediated Oxidative Stress, Low-Grade Endotoxemia, Hypoalbuminemia, and Clotting Activation in COVID-19. Antioxidants (Basel) 2024; 13:1260. [PMID: 39456513 PMCID: PMC11505442 DOI: 10.3390/antiox13101260] [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: 09/25/2024] [Revised: 10/11/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Low-grade endotoxemia by lipopolysaccharide (LPS) has been detected in COVID-19 and could favor thrombosis via eliciting a pro-inflammatory and pro-coagulant state. The aim of this study was to analyze the mechanism accounting for low-grade endotoxemia and its relationship with oxidative stress and clotting activation thrombosis in COVID-19. We measured serum levels of sNOX2-dp, zonulin, LPS, D-dimer, and albumin in 175 patients with COVID-19, classified as having or not acute respiratory distress syndrome (ARDS), and 50 healthy subjects. Baseline levels of sNOX2-dp, LPS, zonulin, D-dimer, albumin, and hs-CRP were significantly higher in COVID-19 compared to controls. In COVID-19 patients with ARDS, sNOX2-dp, LPS, zonulin, D-dimer, and hs-CRP were significantly higher compared to COVID-19 patients without ARDS. Conversely, concentration of albumin was lower in patients with ARDS compared with those without ARDS and inversely associated with LPS. In the COVID-19 cohort, the number of patients with ARDS progressively increased according to sNOX2-dp and LPS quartiles; a significant correlation between LPS and sNOX2-dp and LPS and D-dimer was detected in COVID-19. In a multivariable logistic regression model, LPS/albumin levels and D-dimer predicted thrombotic events. In COVID-19 patients, LPS is significantly associated with a hypercoagulation state and disease severity. In vitro, LPS can increase endothelial oxidative stress and coagulation biomarkers that were reduced by the treatment with albumin. In conclusion, impaired gut barrier permeability, increased NOX2 activation, and low serum albumin may account for low-grade endotoxemia and may be implicated in thrombotic events in COVID-19.
Collapse
Affiliation(s)
- Roberto Carnevale
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy; (G.E.C.); (G.F.)
- IRCCS Neuromed, 86077 Pozzilli, Italy;
| | - Cristina Nocella
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (C.N.); (P.P.); (F.V.)
| | - Raffaella Marocco
- Infectious Diseases Unit, Santa Maria (SM) Goretti Hospital, Sapienza University of Rome, 04100 Latina, Italy; (R.M.); (P.Z.); (C.D.B.)
| | - Paola Zuccalà
- Infectious Diseases Unit, Santa Maria (SM) Goretti Hospital, Sapienza University of Rome, 04100 Latina, Italy; (R.M.); (P.Z.); (C.D.B.)
| | - Anna Carraro
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy; (A.C.); (A.O.); (M.C.M.); (M.D.A.); (F.C.); (M.V.); (C.M.M.); (M.L.)
| | | | - Alessandra Oliva
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy; (A.C.); (A.O.); (M.C.M.); (M.D.A.); (F.C.); (M.V.); (C.M.M.); (M.L.)
| | - Roberto Cangemi
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (R.C.); (L.R.); (D.A.); (V.C.)
| | - Maria Claudia Miele
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy; (A.C.); (A.O.); (M.C.M.); (M.D.A.); (F.C.); (M.V.); (C.M.M.); (M.L.)
| | - Massimiliano De Angelis
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy; (A.C.); (A.O.); (M.C.M.); (M.D.A.); (F.C.); (M.V.); (C.M.M.); (M.L.)
| | - Francesca Cancelli
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy; (A.C.); (A.O.); (M.C.M.); (M.D.A.); (F.C.); (M.V.); (C.M.M.); (M.L.)
| | - Giovanni Enrico Casciaro
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy; (G.E.C.); (G.F.)
| | | | - Pasquale Pignatelli
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (C.N.); (P.P.); (F.V.)
| | - Giacomo Frati
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy; (G.E.C.); (G.F.)
- IRCCS Neuromed, 86077 Pozzilli, Italy;
| | - Mario Venditti
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy; (A.C.); (A.O.); (M.C.M.); (M.D.A.); (F.C.); (M.V.); (C.M.M.); (M.L.)
| | - Francesco Pugliese
- Department of General Surgery and Surgical Specialty, Sapienza University of Rome, 00161 Rome, Italy;
| | - Claudio Maria Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy; (A.C.); (A.O.); (M.C.M.); (M.D.A.); (F.C.); (M.V.); (C.M.M.); (M.L.)
| | - Francesco Violi
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (C.N.); (P.P.); (F.V.)
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (R.C.); (L.R.); (D.A.); (V.C.)
| | - Cosmo Del Borgo
- Infectious Diseases Unit, Santa Maria (SM) Goretti Hospital, Sapienza University of Rome, 04100 Latina, Italy; (R.M.); (P.Z.); (C.D.B.)
| | - Silvia Palmerio
- Centro Ricerche Cliniche di Verona (CRC), 37134 Verona, Italy;
| | | | - Rita Carnevale
- Corso di Laurea di I Livello in Infermieristica, Università Sapienza di Roma–Polo Pontino–Sede di Terracina, 04019 Terracina, Italy;
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (R.C.); (L.R.); (D.A.); (V.C.)
| | - Miriam Lichtner
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy; (A.C.); (A.O.); (M.C.M.); (M.D.A.); (F.C.); (M.V.); (C.M.M.); (M.L.)
| | - Vincenzo Cardinale
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy; (R.C.); (L.R.); (D.A.); (V.C.)
| |
Collapse
|
|
5
|
Pellicano C, Oliva A, Colalillo A, Gigante A, D'Aliesio E, Al Ismail D, Miele MC, Cianci R, Mastroianni CM, Rosato E. Serum markers of microbial translocation and intestinal damage in assessment of gastrointestinal tract involvement in systemic sclerosis. Clin Exp Med 2024; 24:225. [PMID: 39294494 PMCID: PMC11410972 DOI: 10.1007/s10238-024-01466-1] [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: 07/04/2024] [Accepted: 08/14/2024] [Indexed: 09/20/2024]
Abstract
Gastrointestinal (GI) tract involvement affects up to 90% of Systemic sclerosis (SSc) patients. The presence of GI symptoms is assessed by the University of California, Los Angeles, and Scleroderma Clinical Trials Consortium Gastrointestinal Scale (UCLA SCTC GIT 2.0). Microbial translocation (MT) is reported in SSc patients consequently to increased intestinal permeability due to intestinal damage (ID) and dysbiosis. Aim of this study was to assess circulating levels of LBP and EndoCab IgM (markers of MT), IL-6 (marker of inflammation), I-FABP and Zonulin (markers of ID) in a cohort of SSc patients and healthy controls (HC). Moreover, we aimed to correlate these parameters with severity of GI symptoms. UCLA SCTC GIT 2.0 questionnaire was administered to 60 consecutive SSc patients. Markers of MT, inflammation and ID were evaluated in SSc patients and HC. SSc patients had higher median value of markers of MT, inflammation and ID than HC. The logistic regression analysis showed LBP as the only variable associated with an UCLA total score "moderate-to-very severe" [OR 1.001 (CI 95%: 1.001-1.002), p < 0.001]. The logistic regression analysis showed LBP [OR 1.002 (CI 95%: 1.001-1.003), p < 0.01] and disease duration [OR 1.242 (CI 95%: 1.023-1.506), p < 0.05] as variables associated with UCLA distension/bloating "moderate-to-very severe". The logistic regression analysis showed LBP as the only variable associated with UCLA diarrhea "moderate-to-very severe" [OR 1.002 (CI 95%: 1.001-1.003), p < 0.01]. SSc patients with dysregulation gut mucosal integrity expressed by high levels of MT and ID biomarkers had more severe GI symptoms.
Collapse
Affiliation(s)
- Chiara Pellicano
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy
| | - Alessandra Oliva
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy
| | - Amalia Colalillo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy
| | - Antonietta Gigante
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy
| | - Elisa D'Aliesio
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy
| | - Dania Al Ismail
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy
| | - Maria Claudia Miele
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy
| | - Rosario Cianci
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy
| | - Claudio Maria Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy
| | - Edoardo Rosato
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy.
| |
Collapse
|
|
6
|
Merk D, Cox FF, Jakobs P, Prömel S, Altschmied J, Haendeler J. Dose-Dependent Effects of Lipopolysaccharide on the Endothelium-Sepsis versus Metabolic Endotoxemia-Induced Cellular Senescence. Antioxidants (Basel) 2024; 13:443. [PMID: 38671891 PMCID: PMC11047739 DOI: 10.3390/antiox13040443] [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: 02/19/2024] [Revised: 04/03/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
The endothelium, the innermost cell layer of blood vessels, is not only a physical barrier between the bloodstream and the surrounding tissues but has also essential functions in vascular homeostasis. Therefore, it is not surprising that endothelial dysfunction is associated with most cardiovascular diseases. The functionality of the endothelium is compromised by endotoxemia, the presence of bacterial endotoxins in the bloodstream with the main endotoxin lipopolysaccharide (LPS). Therefore, this review will focus on the effects of LPS on the endothelium. Depending on the LPS concentration, the outcomes are either sepsis or, at lower concentrations, so-called low-dose or metabolic endotoxemia. Sepsis, a life-threatening condition evoked by hyperactivation of the immune response, includes breakdown of the endothelial barrier resulting in failure of multiple organs. A deeper understanding of the underlying mechanisms in the endothelium might help pave the way to new therapeutic options in sepsis treatment to prevent endothelial leakage and fatal septic shock. Low-dose endotoxemia or metabolic endotoxemia results in chronic inflammation leading to endothelial cell senescence, which entails endothelial dysfunction and thus plays a critical role in cardiovascular diseases. The identification of compounds counteracting senescence induction in endothelial cells might therefore help in delaying the onset or progression of age-related pathologies. Interestingly, two natural plant-derived substances, caffeine and curcumin, have shown potential in preventing endothelial cell senescence.
Collapse
Affiliation(s)
- Dennis Merk
- Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany; (D.M.); (F.F.C.); (P.J.)
| | - Fiona Frederike Cox
- Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany; (D.M.); (F.F.C.); (P.J.)
- Medical Faculty, Institute for Translational Pharmacology, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Philipp Jakobs
- Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany; (D.M.); (F.F.C.); (P.J.)
| | - Simone Prömel
- Department of Biology, Institute of Cell Biology, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
| | - Joachim Altschmied
- Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany; (D.M.); (F.F.C.); (P.J.)
- Medical Faculty, Cardiovascular Research Institute Düsseldorf, CARID, University Hospital and Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
| | - Judith Haendeler
- Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine-University, 40225 Düsseldorf, Germany; (D.M.); (F.F.C.); (P.J.)
- Medical Faculty, Cardiovascular Research Institute Düsseldorf, CARID, University Hospital and Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
| |
Collapse
|
|
7
|
Violi F, Harenberg J, Pignatelli P, Cammisotto V. COVID-19 and Long-COVID Thrombosis: From Clinical and Basic Science to Therapeutics. Thromb Haemost 2024; 124:286-296. [PMID: 37967846 DOI: 10.1055/s-0043-1776713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2023]
Abstract
Coronavirus infectious disease-19 (COVID-19) is a pandemic characterized by serious lung disease and thrombotic events in the venous and circulation trees, which represent a harmful clinical sign of poor outcome. Thrombotic events are more frequent in patients with severe disease requiring intensive care units and are associated with platelet and clotting activation. However, after resolution of acute infection, patients may still have clinical sequelae, the so-called long-COVID-19, including thrombotic events again in the venous and arterial circulation. The mechanisms accounting for thrombosis in acute and long COVID-19 have not been fully clarified; interactions of COVID-19 with angiotensin converting enzyme 2 or toll-like receptor family or infection-induced cytokine storm have been suggested to be implicated in endothelial cells, leucocytes, and platelets to elicit clotting activation in acute as well in chronic phase of the disease. In acute COVID-19, prophylactic or full doses of anticoagulants exert beneficial effects even if the dosage choice is still under investigation; however, a residual risk still remains suggesting a need for a more appropriate therapeutic approach. In long COVID-19 preliminary data provided useful information in terms of antiplatelet treatment but definition of candidates for thrombotic prophylaxis is still undefined.
Collapse
Affiliation(s)
- Francesco Violi
- Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
- Mediterranea Cardiocentro, Via Orazio, Naples, Italy
| | - Job Harenberg
- Medical Faculty Mannheim, Ruprecht-karls University Heidelberg, Heidelberg, Germany
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
- Mediterranea Cardiocentro, Via Orazio, Naples, Italy
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| |
Collapse
|
|
8
|
Cangemi R, Carnevale R, Nocella C, Calvieri C, Bartimoccia S, Frati G, Pignatelli P, Picchio V, Violi F. Low-grade endotoxemia is associated with cardiovascular events in community-acquired pneumonia. J Infect 2024; 88:89-94. [PMID: 38000675 DOI: 10.1016/j.jinf.2023.11.010] [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: 09/27/2023] [Revised: 11/16/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023]
Abstract
OBJECTIVES Community-acquired pneumonia (CAP) is associated with low-grade endotoxemia but its relationship with cardiovascular events (CVE) has not been investigated. METHODS We evaluated the incidence of CVE including myocardial infarction, stroke, and cardiovascular death in 523 adult patients hospitalized for CAP. Serum lipopolysaccharide (LPS) and zonulin, a marker of gut permeability, were analyzed in the cohort, that was followed-up during hospitalization and up to 43 months thereafter. RESULTS During the hospital-stay, 55 patients experienced CVE with a progressive increase from the lowest (0.6%) to highest LPS tertile (23.6%, p < 0.001). Logistic regression analyses showed that higher LPS tertile was independently associated with CVE; LPS significantly correlated with age, hs-CRP and zonulin. In a sub-group of 23 CAP patients, blood E. coli DNA was higher in patients compared to 24 controls and correlated with LPS. During the long-term follow-up, 102 new CVE were registered; the highest tertile of LPS levels was associated with incident CVE; Cox regression analysis showed that LPS tertiles, age, history of CHD, and diabetes independently predicted CVE. CONCLUSIONS In CAP low-grade endotoxemia is associated to short- and long-term risk of CVE. Further study is necessary to assess if lowering LPS by non-absorbable antibiotics may result in improved outcomes.
Collapse
Affiliation(s)
- Roberto Cangemi
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Roberto Carnevale
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica, Latina, Italy; IRCCS Neuromed, Località Camerelle, Pozzilli, Isernia, Italy
| | - Cristina Nocella
- Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Camilla Calvieri
- Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Simona Bartimoccia
- Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Giacomo Frati
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica, Latina, Italy; IRCCS Neuromed, Località Camerelle, Pozzilli, Isernia, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy; Mediterranea Cardiocentro-Napoli, Naples, Italy
| | - Vittorio Picchio
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica, Latina, Italy; IRCCS Neuromed, Località Camerelle, Pozzilli, Isernia, Italy
| | - Francesco Violi
- Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy; Mediterranea Cardiocentro-Napoli, Naples, Italy.
| |
Collapse
|
|
9
|
Ząbczyk M, Kruk A, Natorska J, Undas A. Low-grade endotoxemia in acute pulmonary embolism: Links with prothrombotic plasma fibrin clot phenotype. Thromb Res 2023; 232:70-76. [PMID: 37949000 DOI: 10.1016/j.thromres.2023.10.020] [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: 08/29/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND Lipopolysaccharide (LPS) can traverse the intestinal barrier and enter bloodstream, causing endotoxemia and triggering inflammation. Increased circulating LPS was reported in arterial thromboembolism. We investigated whether increased LPS levels occur in acute pulmonary embolism (PE) and if it is associated with a prothrombotic state. METHODS We studied 120 normotensive PE patients (aged 59 [48-68] years) on admission, after 5-7 days, and after a 3-month anticoagulation. Serum LPS levels, along with zonulin, a marker of gut permeability, endogenous thrombin potential (ETP), fibrin clot permeability (Ks), clot lysis time (CLT), fibrinolysis proteins, and platelet markers were assessed. RESULTS Median LPS concentration on admission was 70.5 (61.5-82) pg/mL (min-max, 34-134 pg/mL), in association with C-reactive protein (r = 0.22, p = 0.018), but not with fibrinogen, D-dimer or platelet markers. Patients with more severe PE had higher LPS levels compared with the remainder. Median zonulin level was 3.26 (2.74-4.08) ng/mL and correlated with LPS (r = 0.66, p < 0.0001). Patients with baseline LPS levels in the top quartile (≥82 pg/mL; n = 29) compared to lower quartiles had 18.6 % increased ETP, 14.5 % reduced Ks, and 25.3 % prolonged CLT, related to higher plasminogen activator inhibitor type 1 (PAI-1) levels. LPS decreased by 23.4 % after 5-7 days and by 40.4 % after 3-month anticoagulation together with reduced zonulin by 18.4 % and 22.3 %, respectively, compared to baseline (all p < 0.001). LPS levels were not related with fibrin characteristics and other variables assessed at 3 months. CONCLUSIONS Low-grade endotoxemia is detectable in patients with acute PE and may contribute to increased thrombin generation and PAI-1-mediated hypofibrinolysis.
Collapse
Affiliation(s)
- Michał Ząbczyk
- St. John Paul II Hospital, Kraków, Poland; Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland
| | | | - Joanna Natorska
- St. John Paul II Hospital, Kraków, Poland; Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland
| | - Anetta Undas
- St. John Paul II Hospital, Kraków, Poland; Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland.
| |
Collapse
|
|
10
|
Papa A, Santini P, De Lucia SS, Maresca R, Porfidia A, Pignatelli P, Gasbarrini A, Violi F, Pola R. Gut dysbiosis-related thrombosis in inflammatory bowel disease: Potential disease mechanisms and emerging therapeutic strategies. Thromb Res 2023; 232:77-88. [PMID: 37951044 DOI: 10.1016/j.thromres.2023.11.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/23/2023] [Accepted: 11/03/2023] [Indexed: 11/13/2023]
Abstract
Patients with inflammatory bowel disease (IBD) have an increased risk of developing venous thromboembolic events, which have a considerable impact on morbidity and mortality. Chronic inflammation plays a crucial role in the pathogenesis of thrombotic events in patients with IBD. However, many unresolved questions remain, particularly regarding the mechanisms that determine the persistent inflammatory state independent of disease activity. This review explored the role of gut microbiota dysbiosis and intestinal barrier dysfunction, which are considered distinctive features of IBD, in determining pro-thrombotic tendencies. Gut-derived endotoxemia due to the translocation of bacterial lipopolysaccharides (LPS) from the intestine to the bloodstream and the bacterial metabolite trimethylamine-N-oxide (TMAO) are the most important molecules involved in gut dysbiosis-related thrombosis. The pathogenic prothrombotic pathways linked to LPS and TMAO have been discussed. Finally, we present emerging therapeutic approaches that can help reduce LPS-mediated endotoxemia and TMAO, such as restoring intestinal eubiosis, normalizing intestinal barrier function, and counterbalancing the effects of LPS and TMAO.
Collapse
Affiliation(s)
- Alfredo Papa
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Agostino Gemelli University Polyclinic Foundation IRCCS, Rome, Italy; Department of Translational Medicine and Surgery, Catholic University of Sacred Heart, Rome, Italy.
| | - Paolo Santini
- Department of Translational Medicine and Surgery, Catholic University of Sacred Heart, Rome, Italy; Thrombosis Clinic, Agostino Gemelli University Polyclinic Foundation IRCCS, Rome, Italy
| | - Sara Sofia De Lucia
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Agostino Gemelli University Polyclinic Foundation IRCCS, Rome, Italy; Department of Translational Medicine and Surgery, Catholic University of Sacred Heart, Rome, Italy
| | - Rossella Maresca
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Agostino Gemelli University Polyclinic Foundation IRCCS, Rome, Italy; Department of Translational Medicine and Surgery, Catholic University of Sacred Heart, Rome, Italy
| | - Angelo Porfidia
- Department of Translational Medicine and Surgery, Catholic University of Sacred Heart, Rome, Italy; Thrombosis Clinic, Agostino Gemelli University Polyclinic Foundation IRCCS, Rome, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy; Mediterranea Cardiocentro-Napoli, Naples, Italy
| | - Antonio Gasbarrini
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Agostino Gemelli University Polyclinic Foundation IRCCS, Rome, Italy; Department of Translational Medicine and Surgery, Catholic University of Sacred Heart, Rome, Italy
| | - Francesco Violi
- Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy; Mediterranea Cardiocentro-Napoli, Naples, Italy
| | - Roberto Pola
- Department of Translational Medicine and Surgery, Catholic University of Sacred Heart, Rome, Italy; Thrombosis Clinic, Agostino Gemelli University Polyclinic Foundation IRCCS, Rome, Italy
| |
Collapse
|
|
11
|
Isaza-Correa J, Ryan L, Kelly L, Allen J, Melo A, Jones J, Huggard D, Ryan E, Ó Maoldomhnaigh C, Geoghehan S, Gavin P, Leahy TR, Butler K, Freyne B, Molloy EJ. Innate immune dysregulation in multisystem inflammatory syndrome in children (MIS-C). Sci Rep 2023; 13:16463. [PMID: 37777557 PMCID: PMC10542373 DOI: 10.1038/s41598-023-43390-6] [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: 06/12/2023] [Accepted: 09/22/2023] [Indexed: 10/02/2023] Open
Abstract
MIS-C is a systemic inflammation disorder with poorly characterised immunopathological mechanisms. We compared changes in the systemic immune response in children with MIS-C (n = 12, 5-13 years) to healthy controls (n = 14, 5-15 years). Analysis was done in whole blood treated with LPS. Expression of CD11b and Toll-like receptor-4 (TLR4) in neutrophils and monocytes were analysed by flow cytometry. Serum cytokines (IL-1β, IL-2, IL-6, IL-8, IL-10, IL-Ira, TNF-α, TNF-β, IFN-Υ, VEGF, EPO and GM-CSF) and mRNA levels of inflammasome molecules (NLRP3, ASC and IL-1β) were evaluated. Subpopulations of lymphocytes (CD3+, CD19+, CD56+, CD4+, CD8+, TCR Vδ1+, TCR Vδ2+) were assessed at basal levels. Absolute counts of neutrophils and NLR were high in children with MIS-C while absolute counts of lymphocytes were low. Children with MIS-C had increased levels of IL-6, IL-10, TNF-β and VEGF serum cytokines at the basal level, and significantly increased TNF-β post-LPS, compared to controls. IL-1RA and EPO decreased at baseline and post-LPS in MIS-C patients compared to controls. The percentage of CD3+ cells, NK cells and Vδ1 was lower while B cells were higher in children with MIS-C than in controls. Dysregulated immune response in children with MIS-C was evident and may be amenable to immunomodulation.
Collapse
Affiliation(s)
- Johana Isaza-Correa
- Discipline of Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland
- Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity Research in Childhood Centre (TRiCC), Trinity College Dublin, Dublin, Ireland
| | - Laura Ryan
- Discipline of Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland
- Trinity Research in Childhood Centre (TRiCC), Trinity College Dublin, Dublin, Ireland
| | - Lynne Kelly
- Discipline of Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland
- Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity Research in Childhood Centre (TRiCC), Trinity College Dublin, Dublin, Ireland
| | - John Allen
- Discipline of Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland
- Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity Research in Childhood Centre (TRiCC), Trinity College Dublin, Dublin, Ireland
| | - Ashanty Melo
- Discipline of Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland
- Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity Research in Childhood Centre (TRiCC), Trinity College Dublin, Dublin, Ireland
| | - Jennifer Jones
- Infectious Diseases/Immunology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Dean Huggard
- Discipline of Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland
- Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity Research in Childhood Centre (TRiCC), Trinity College Dublin, Dublin, Ireland
| | - Emer Ryan
- Discipline of Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland
- Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity Research in Childhood Centre (TRiCC), Trinity College Dublin, Dublin, Ireland
| | | | - Sarah Geoghehan
- Infectious Diseases/Immunology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Patrick Gavin
- Infectious Diseases/Immunology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Timothy Ronan Leahy
- Discipline of Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland
- Infectious Diseases/Immunology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Karina Butler
- Infectious Diseases/Immunology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Bridget Freyne
- Infectious Diseases/Immunology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Eleanor J Molloy
- Discipline of Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland.
- Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
- Trinity Research in Childhood Centre (TRiCC), Trinity College Dublin, Dublin, Ireland.
- Infectious Diseases/Immunology, Children's Health Ireland at Crumlin, Dublin, Ireland.
- Neonatology, Children's Health Ireland at Crumlin, Dublin, Ireland.
- Neurodisability, Children's Health Ireland at Tallaght, Dublin, Ireland.
- Neonatology, The Coombe Hospital, Dublin, Ireland.
- Discipline of Paediatrics, Trinity Centre for Health Sciences, Children's Hospital Ireland (CHI) at Tallaght, Tallaght University Hospital, Dublin 24, Ireland.
| |
Collapse
|
|
12
|
Cogliati Dezza F, Covino S, Petrucci F, Sacco F, Viscido A, Gavaruzzi F, Ceccarelli G, Raponi G, Borrazzo C, Alessandri F, Mastroianni CM, Venditti M, Oliva A. Risk factors for carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infections and related mortality in critically ill patients with CRAB colonization. JAC Antimicrob Resist 2023; 5:dlad096. [PMID: 37577156 PMCID: PMC10412853 DOI: 10.1093/jacamr/dlad096] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/21/2023] [Indexed: 08/15/2023] Open
Abstract
Background Among MDR bacteria, carbapenem-resistant Acinetobacter baumannii (CRAB) is a major concern due to the limited therapeutic options. During the COVID-19 pandemic, a worrying increase in the spread of CRAB infections was reported. Objectives The study assessed the risk factors for CRAB bloodstream infection (BSI) in patients admitted to the ICU with CRAB colonization, and the related mortality risk factors. Methods We conducted a single-centre, observational, prospective study; all consecutive patients with CRAB colonization admitted to the ICU of a tertiary hospital in Rome from January 2021 to September 2022 were included in the study. Univariate and multivariate analyses were performed to investigate BSI and mortality risk factors. Results Overall, 129 patients were included in the study; 57 (44%) out of these developed BSI. In our study population, at the multivariable analysis the Charlson comorbidity index (CCI) (P = 0.026), COVID-19 (P < 0.001), multisite colonization (P = 0.016) and the need for mechanical ventilation (P = 0.024) were risk factors independently associated with BSI development. Furthermore, age (P = 0.026), CCI (P < 0.001), septic shock (P = 0.001) and Pitt score (P < 0.001) were independently associated with mortality in the BSI patients. Instead, early appropriate therapy (P = 0.002) and clinical improvement within 72 h (P = 0.011) were shown to be protective factors. Conclusions In critically ill patients colonized by CRAB, higher CCI, multisite colonization and the need for mechanical ventilation were identified as risk factors for BSI onset. These predictors could be useful to identify patients at highest risk of BSI.
Collapse
Affiliation(s)
| | - Sara Covino
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Flavia Petrucci
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Federica Sacco
- Microbiology and Virology Laboratory, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Agnese Viscido
- Microbiology and Virology Laboratory, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesca Gavaruzzi
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Gianmarco Raponi
- Microbiology and Virology Laboratory, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Cristian Borrazzo
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Francesco Alessandri
- Department of General and Specialistic Surgery, Sapienza University of Rome, Rome, Italy
| | | | - Mario Venditti
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Alessandra Oliva
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| |
Collapse
|
|
13
|
Singh R, Malik P, Kumar M, Kumar R, Alam MS, Mukherjee TK. Secondary fungal infections in SARS-CoV-2 patients: pathological whereabouts, cautionary measures, and steadfast treatments. Pharmacol Rep 2023:10.1007/s43440-023-00506-z. [PMID: 37354313 DOI: 10.1007/s43440-023-00506-z] [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: 02/09/2023] [Revised: 06/09/2023] [Accepted: 06/12/2023] [Indexed: 06/26/2023]
Abstract
The earliest documented COVID-19 case caused by the SARS-CoV-2 coronavirus occurred in Wuhan, China, in December 2019. Since then, several SARS-CoV-2 mutants have rapidly disseminated as exemplified by the community spread of the recent omicron variant. The disease already attained a pandemic status with ever-dwindling mortality even after two and half years of identification and considerable vaccination. Aspergillosis, candidiasis, cryptococcosis and mucormycosis are the prominent fungal infections experienced by the majority of SARS-CoV-2 high-risk patients. In its entirety, COVID-19's nexus with these fungal infections may worsen the intricacies in the already beleaguered high-risk patients, making this a topic of substantial clinical concern. Thus, thorough knowledge of the subject is necessary. This article focuses on the concomitant fungal infection(s) in COVID-19 patients, taking into account their underlying causes, the screening methods, manifested drug resistance, and long-term effects. The information and knowledge shared herein could be crucial for the management of critically ill, aged, and immunocompromised SARS-CoV-2 patients who have had secondary fungal infections (SFIs).
Collapse
Affiliation(s)
- Raj Singh
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, Haryana, 133207, India
| | - Parth Malik
- School of Chemical Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India
| | - Mukesh Kumar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, Haryana, 133207, India
| | - Raman Kumar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, Haryana, 133207, India
| | - Md Shamshir Alam
- Department of Pharmacy Practice, College of Pharmacy, National University of Science and Technology, PO Box 620, 130, Bosher-Muscat, Sultanate of Oman
| | - Tapan Kumar Mukherjee
- Amity Institute of Biotechnology, Amity University, Sector-125, Noida, UP, India.
- Department of Biotechnology, Amity University, Major Arterial Road, Action Area II, Rajarhat, New Town, Kolkata, West Bengal, 700135, India.
| |
Collapse
|
|
14
|
Ciacci P, Paraninfi A, Orlando F, Rella S, Maggio E, Oliva A, Cangemi R, Carnevale R, Bartimoccia S, Cammisotto V, D'Amico A, Magna A, Nocella C, Mastroianni CM, Pignatelli P, Violi F, Loffredo L. Endothelial dysfunction, oxidative stress and low-grade endotoxemia in COVID-19 patients hospitalised in medical wards. Microvasc Res 2023:104557. [PMID: 37268038 DOI: 10.1016/j.mvr.2023.104557] [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: 02/09/2023] [Revised: 05/19/2023] [Accepted: 05/30/2023] [Indexed: 06/04/2023]
Abstract
BACKGROUND Endothelial dysfunction, assessed by flow-mediated dilation (FMD), is related to poor prognosis in patients with COVID-19 pneumonia (CP). In this study, we explored the interplay among FMD, NADPH oxidase type 2 (NOX-2) and lipopolysaccharides (LPS) in hospitalised patients with CP, community acquired pneumonia (CAP) and controls (CT). METHODS We enrolled 20 consecutive patients with CP, 20 hospitalised patients with CAP and 20 CT matched for sex, age, and main cardiovascular risk factors. In all subjects we performed FMD and collected blood samples to analyse markers of oxidative stress (soluble Nox2-derived peptide (sNOX2-dp), hydrogen peroxide breakdown activity (HBA), nitric oxide (NO), hydrogen peroxide (H2O2)), inflammation (TNF-α and IL-6), LPS and zonulin levels. RESULTS Compared with controls, CP had significant higher values of LPS, sNOX-2-dp, H2O2,TNF-α, IL-6 and zonulin; conversely FMD, HBA and NO bioavailability were significantly lower in CP. Compared to CAP patients, CP had significantly higher levels of sNOX2-dp, H2O2, TNF-α, IL-6, LPS, zonulin and lower HBA. Simple linear regression analysis showed that FMD inversely correlated with sNOX2-dp, H2O2, TNF-α, IL-6, LPS and zonulin; conversely FMD was directly correlated with NO bioavailability and HBA. Multiple linear regression analysis highlighted LPS as the only predictor of FMD. CONCLUSION This study shows that patients with COVID-19 have low-grade endotoxemia that could activate NOX-2, generating increased oxidative stress and endothelial dysfunction.
Collapse
Affiliation(s)
- Paolo Ciacci
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Aurora Paraninfi
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Federica Orlando
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Silvia Rella
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Enrico Maggio
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Alessandra Oliva
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Roberto Cangemi
- Department of Translational and Precision Medicine, Sapienza-University of Rome, Viale del Policlinico 155, 00162 Rome, Italy
| | - Roberto Carnevale
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; Mediterranea Cardiocentro, Naples, Italy
| | - Simona Bartimoccia
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Alessandra D'Amico
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", 00135 Rome, Italy
| | - Arianna Magna
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Cristina Nocella
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Claudio Maria Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Francesco Violi
- Mediterranea Cardiocentro, Naples, Italy; Sapienza University of Rome, Rome, Italy
| | - Lorenzo Loffredo
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy.
| |
Collapse
|
|
15
|
Abstract
COVID-19 is characterized by dysregulated thrombosis and coagulation that can increase mortality in patients. Platelets are fast responders to pathogen presence, alerting the surrounding immune cells and contributing to thrombosis and intravascular coagulation. The SARS-CoV-2 genome has been found in platelets from patients with COVID-19, and its coverage varies according to the method of detection, suggesting direct interaction of the virus with these cells. Antibodies against Spike and Nucleocapsid have confirmed this platelet-viral interaction. This review discusses the immune, prothrombotic, and procoagulant characteristics of platelets observed in patients with COVID-19. We outline the direct and indirect interaction of platelets with SARS-CoV-2, the contribution of the virus to programmed cell death pathway activation in platelets and the consequent extracellular vesicle release. We discuss platelet activation and immunothrombosis in patients with COVID-19, the effect of Spike on platelets, and possible activation of platelets by classical platelet activation triggers as well as contribution of platelets to complement activation. As COVID-19-mediated thrombosis and coagulation are still not well understood in vivo, we discuss available murine models and mouse adaptable strains.
Collapse
Affiliation(s)
- Anthony Sciaudone
- Department of Medicine, Divisions of Cardiovascular Medicine (A.S., H.C., M.K.), University of Massachusetts Chan Medical School, Worcester, MA
| | - Heather Corkrey
- Department of Medicine, Divisions of Cardiovascular Medicine (A.S., H.C., M.K.), University of Massachusetts Chan Medical School, Worcester, MA
| | - Fiachra Humphries
- Innate Immunity (F.H.). University of Massachusetts Chan Medical School, Worcester, MA
| | - Milka Koupenova
- Department of Medicine, Divisions of Cardiovascular Medicine (A.S., H.C., M.K.), University of Massachusetts Chan Medical School, Worcester, MA
| |
Collapse
|
|
16
|
Kozlov KV, Zhdanov KV, Ratnikova AK, Ratnikov VA, Tishkov AV, Grinevich V, Kravchuk YA, Miklush PI, Nikiforova PO, Gordienko VV, Popov AF, Andryukov BG. Hepatobiliary system and intestinal injury in new coronavirus infection (COVID-19): A retrospective study. World J Clin Cases 2023; 11:2226-2236. [PMID: 37122523 PMCID: PMC10131012 DOI: 10.12998/wjcc.v11.i10.2226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/22/2023] [Accepted: 03/06/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND An important area of effective control of the coronavirus disease 19 (COVID-19) pandemic is the study of the pathogenic features of severe acute respiratory syndrome coronavirus 2 infection, including those based on assessing the state of the intestinal microbiota and permeability.
AIM To study the clinical features of the new COVID-19 in patients with mild and moderate severity at the stage of hospitalization, to determine the role of hepatobiliary injury, intestinal permeability disorders, and changes in the qualitative and quantitative composition of the microbiota in the development of systemic inflammation in patients with COVID-19.
METHODS The study was performed in 80 patients with COVID-19, with an average age of 45 years, 19 of whom had mild disease, and 61 had moderate disease severity. The scope of the examination included traditional clinical, laboratory, biochemical, instrumental, and radiation studies, as well as original methods for studying microbiota and intestinal permeability.
RESULTS The clinical course of COVID-19 was studied, and the clinical and biochemical features, manifestations of systemic inflammation, and intestinal microbiome changes in patients with mild and moderate severity were identified. Intestinal permeability characteristics against the background of COVID-19 were evaluated by measuring levels of proinflammatory cytokines, insulin, faecal calprotectin, and zonulin.
CONCLUSION This study highlights the role of intestinal permeability and microbiota as the main drivers of gastroenterological manifestations and increased COVID-19 severity.
Collapse
Affiliation(s)
- Konstantin V Kozlov
- Department of Infectious Disease, Military Medical Academy Named After SM. Kirov, Saint-Petersburg 194044, Russia
| | - Konstantin V Zhdanov
- Department of Infectious Disease, Military Medical Academy Named After SM. Kirov, Saint-Petersburg 194044, Russia
| | - Anna K Ratnikova
- Department of Admission, Federal State Budgetary Institution "North-West District Scientific and Clinical Center Named After LG. Sokolov Federal Medical and Biological Agency", Saint-Petersburg 194291, Russia
| | - Vyacheslav A Ratnikov
- Department of Roentgenology, Federal State Budgetary Institution "North-West District Scientific and Clinical Center Named After LG. Sokolov Federal Medical and Biological Agency", Saint-Petersburg 194291, Russia
| | - Artem V Tishkov
- Department of Physics, Mathematics and Informatics, FSBEI HE IP. Pavlov SPbSMU MOH Russia, Saint-Petersburg 197022, Russia
| | - Vladimir Grinevich
- 2nd Department of Therapy (Advanced Medical Education), Military Medical Academy Named After SM. Kirov, Saint-Petersburg 194044, Russia
| | - Yuriy A Kravchuk
- Department of Infectious Disease, Military Medical Academy Named After SM. Kirov, Saint-Petersburg 194044, Russia
| | - Panteley I Miklush
- Department of Infectious Disease, Military Medical Academy Named After SM. Kirov, Saint-Petersburg 194044, Russia
| | - Polina O Nikiforova
- Department of Infectious Disease, Military Medical Academy Named After SM. Kirov, Saint-Petersburg 194044, Russia
| | - Vera V Gordienko
- Department of Infectious Disease, Military Medical Academy Named After SM. Kirov, Saint-Petersburg 194044, Russia
| | - Alexander F Popov
- School of Medicine, Far Eastern Federal University, Vladivostok 690922, Russia
| | - Boris G Andryukov
- School of Medicine, Far Eastern Federal University, Vladivostok 690922, Russia
| |
Collapse
|
|
17
|
Zhu W, Wang M, Jin L, Yang B, Bai B, Mutsinze RN, Zuo W, Chattipakorn N, Huh JY, Liang G, Wang Y. Licochalcone A protects against LPS-induced inflammation and acute lung injury by directly binding with myeloid differentiation factor 2 (MD2). Br J Pharmacol 2023; 180:1114-1131. [PMID: 36480410 DOI: 10.1111/bph.15999] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 09/07/2022] [Accepted: 09/12/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a challenging clinical syndrome that leads to various respiratory sequelae and even high mortality in patients with severe disease. The novel pharmacological strategies and therapeutic drugs are urgently needed. Natural products have played a fundamental role and provided an abundant pool in drug discovery. EXPERIMENTAL APPROACH A compound library containing 160 natural products was used to screen potential anti-inflammatory compounds. Mice with LPS-induced ALI was then used to verify the preventive and therapeutic effects of the selected compounds. KEY RESULTS Licochalcone A was discovered from the anti-inflammatory screening of natural products in macrophages. A qPCR array validated the inflammation-regulatory effects of licochalcone A and indicated that the potential targets of licochalcone A may be the upstream proteins in LPS pro-inflammatory signalling. Further studies showed that licochalcone A directly binds to myeloid differentiation factor 2 (MD2), an assistant protein of toll-like receptor 4 (TLR4), to block both LPS-induced TRIF- and MYD88-dependent pathways. LEU61 and PHE151 in MD2 protein are the two key residues that contribute to the binding of MD2 to licochalcone A. In vivo, licochalcone A treatment alleviated ALI in LPS-challenged mice through significantly reducing immunocyte infiltration, suppressing activation of TLR4 pathway and inflammatory cytokine induction. CONCLUSION AND IMPLICATIONS In summary, our study identified MD2 as a direct target of licochalcone A for its anti-inflammatory activity and suggested that licochalcone A might serve as a novel MD2 inhibitor and a potential drug for developing ALI/ARDS therapy.
Collapse
Affiliation(s)
- Weiwei Zhu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.,College of Pharmacy, Chonnam National University, Gwangju, Korea
| | - Minxiu Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Leiming Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Bin Yang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Bin Bai
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Rumbidzai Natasha Mutsinze
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Wei Zuo
- Affiliated Xiangshan Hospital of Wenzhou Medical University (Xiangshan First People's Hospital Medical and Health Group), Xiangshan, China
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Joo Young Huh
- College of Pharmacy, Chonnam National University, Gwangju, Korea
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.,School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.,College of Pharmacy, Chonnam National University, Gwangju, Korea.,Affiliated Xiangshan Hospital of Wenzhou Medical University (Xiangshan First People's Hospital Medical and Health Group), Xiangshan, China
| |
Collapse
|
|
18
|
Tsounis EP, Triantos C, Konstantakis C, Marangos M, Assimakopoulos SF. Intestinal barrier dysfunction as a key driver of severe COVID-19. World J Virol 2023; 12:68-90. [PMID: 37033148 PMCID: PMC10075050 DOI: 10.5501/wjv.v12.i2.68] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/08/2022] [Accepted: 01/16/2023] [Indexed: 03/21/2023] Open
Abstract
The intestinal lumen harbors a diverse consortium of microorganisms that participate in reciprocal crosstalk with intestinal immune cells and with epithelial and endothelial cells, forming a multi-layered barrier that enables the efficient absorption of nutrients without an excessive influx of pathogens. Despite being a lung-centered disease, severe coronavirus disease 2019 (COVID-19) affects multiple systems, including the gastrointestinal tract and the pertinent gut barrier function. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can inflict either direct cytopathic injury to intestinal epithelial and endothelial cells or indirect immune-mediated damage. Alternatively, SARS-CoV-2 undermines the structural integrity of the barrier by modifying the expression of tight junction proteins. In addition, SARS-CoV-2 induces profound alterations to the intestinal microflora at phylogenetic and metabolomic levels (dysbiosis) that are accompanied by disruption of local immune responses. The ensuing dysregulation of the gut-lung axis impairs the ability of the respiratory immune system to elicit robust and timely responses to restrict viral infection. The intestinal vasculature is vulnerable to SARS-CoV-2-induced endothelial injury, which simultaneously triggers the activation of the innate immune and coagulation systems, a condition referred to as “immunothrombosis” that drives severe thrombotic complications. Finally, increased intestinal permeability allows an aberrant dissemination of bacteria, fungi, and endotoxin into the systemic circulation and contributes, to a certain degree, to the over-exuberant immune responses and hyper-inflammation that dictate the severe form of COVID-19. In this review, we aim to elucidate SARS-CoV-2-mediated effects on gut barrier homeostasis and their implications on the progression of the disease.
Collapse
Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Christos Konstantakis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University Hospital of Patras, Patras 26504, Greece
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Patras 26504, Greece
| | - Stelios F Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Patras 26504, Greece
| |
Collapse
|
|
19
|
Carnevale R, Cammisotto V, Bartimoccia S, Nocella C, Castellani V, Bufano M, Loffredo L, Sciarretta S, Frati G, Coluccia A, Silvestri R, Ceccarelli G, Oliva A, Venditti M, Pugliese F, Maria Mastroianni C, Turriziani O, Leopizzi M, D'Amati G, Pignatelli P, Violi F. Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection. Circ Res 2023; 132:290-305. [PMID: 36636919 DOI: 10.1161/circresaha.122.321541] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND SARS-CoV-2 is associated with an increased risk of venous and arterial thrombosis, but the underlying mechanism is still unclear. METHODS We performed a cross-sectional analysis of platelet function in 25 SARS-CoV-2 and 10 healthy subjects by measuring Nox2 (NADPH oxidase 2)-derived oxidative stress and thromboxane B2, and investigated if administration of monoclonal antibodies against the S protein (Spike protein) of SARS-CoV-2 affects platelet activation. Furthermore, we investigated in vitro if the S protein of SARS-CoV-2 or plasma from SARS-CoV-2 enhanced platelet activation. RESULTS Ex vivo studies showed enhanced platelet Nox2-derived oxidative stress and thromboxane B2 biosynthesis and under laminar flow platelet-dependent thrombus growth in SARS-CoV-2 compared with controls; both effects were lowered by Nox2 and TLR4 (Toll-like receptor 4) inhibitors. Two hours after administration of monoclonal antibodies, a significant inhibition of platelet activation was observed in patients with SARS-CoV-2 compared with untreated ones. In vitro study showed that S protein per se did not elicit platelet activation but amplified the platelet response to subthreshold concentrations of agonists and functionally interacted with platelet TLR4. A docking simulation analysis suggested that TLR4 binds to S protein via three receptor-binding domains; furthermore, immunoprecipitation and immunofluorescence showed S protein-TLR4 colocalization in platelets from SARS-CoV-2. Plasma from patients with SARS-CoV-2 enhanced platelet activation and Nox2-related oxidative stress, an effect blunted by TNF (tumor necrosis factor) α inhibitor; this effect was recapitulated by an in vitro study documenting that TNFα alone promoted platelet activation and amplified the platelet response to S protein via p47phox (phagocyte oxidase) upregulation. CONCLUSIONS The study identifies 2 TLR4-dependent and independent pathways promoting platelet-dependent thrombus growth and suggests inhibition of TLR4. or p47phox as a tool to counteract thrombosis in SARS-CoV-2.
Collapse
Affiliation(s)
- Roberto Carnevale
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C., S.S., G.F., M.L.).,IRCCS Neuromed, Località Camerelle, Pozzilli (IS), Italy (R.C., S.S., G.F.)
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences (V. Cammisotto, S.B., C.N., L.L., P.P.), Sapienza University of Rome, Italy
| | - Simona Bartimoccia
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences (V. Cammisotto, S.B., C.N., L.L., P.P.), Sapienza University of Rome, Italy
| | - Cristina Nocella
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences (V. Cammisotto, S.B., C.N., L.L., P.P.), Sapienza University of Rome, Italy
| | - Valentina Castellani
- Department of General Surgery and Surgical Speciality (V. Castellani, F.P.), Sapienza University of Rome, Italy
| | - Marianna Bufano
- Laboratory affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies (M.B., A.C., R.S.), Sapienza University of Rome, Italy
| | - Lorenzo Loffredo
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences (V. Cammisotto, S.B., C.N., L.L., P.P.), Sapienza University of Rome, Italy
| | - Sebastiano Sciarretta
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C., S.S., G.F., M.L.).,IRCCS Neuromed, Località Camerelle, Pozzilli (IS), Italy (R.C., S.S., G.F.)
| | - Giacomo Frati
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C., S.S., G.F., M.L.).,IRCCS Neuromed, Località Camerelle, Pozzilli (IS), Italy (R.C., S.S., G.F.)
| | - Antonio Coluccia
- Laboratory affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies (M.B., A.C., R.S.), Sapienza University of Rome, Italy
| | - Romano Silvestri
- Laboratory affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies (M.B., A.C., R.S.), Sapienza University of Rome, Italy
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases (G.C., A.O., M.V., C.M.M.), Sapienza University of Rome, Italy
| | - Alessandra Oliva
- Department of Public Health and Infectious Diseases (G.C., A.O., M.V., C.M.M.), Sapienza University of Rome, Italy
| | - Mario Venditti
- Department of Public Health and Infectious Diseases (G.C., A.O., M.V., C.M.M.), Sapienza University of Rome, Italy
| | - Francesco Pugliese
- Department of General Surgery and Surgical Speciality (V. Castellani, F.P.), Sapienza University of Rome, Italy
| | - Claudio Maria Mastroianni
- Department of Public Health and Infectious Diseases (G.C., A.O., M.V., C.M.M.), Sapienza University of Rome, Italy
| | - Ombretta Turriziani
- Laboratory of Virology, Department of Molecular Medicine (O.T.), Sapienza University of Rome, Italy
| | - Martina Leopizzi
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C., S.S., G.F., M.L.)
| | - Giulia D'Amati
- Department of Radiological, Oncological and Pathological Sciences (G.D.), Sapienza University of Rome, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences (V. Cammisotto, S.B., C.N., L.L., P.P.), Sapienza University of Rome, Italy.,Mediterranea Cardiocentro- Napoli, Italy (P.P., F.V.)
| | | |
Collapse
|
|
20
|
Dorneles GP, Teixeira PC, Peres A, Rodrigues Júnior LC, da Fonseca SG, Monteiro MC, Eller S, Oliveira TF, Wendland EM, Romão PRT. Endotoxin tolerance and low activation of TLR-4/NF-κB axis in monocytes of COVID-19 patients. J Mol Med (Berl) 2023; 101:183-195. [PMID: 36790534 PMCID: PMC9930695 DOI: 10.1007/s00109-023-02283-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 12/20/2022] [Accepted: 01/03/2023] [Indexed: 02/16/2023]
Abstract
Higher endotoxin in the circulation may indicate a compromised state of host immune response against coinfections in severe COVID-19 patients. We evaluated the inflammatory response of monocytes from COVID-19 patients after lipopolysaccharide (LPS) challenge. Whole blood samples of healthy controls, patients with mild COVID-19, and patients with severe COVID-19 were incubated with LPS for 2 h. Severe COVID-19 patients presented higher LPS and sCD14 levels in the plasma than healthy controls and mild COVID-19 patients. In non-stimulated in vitro condition, severe COVID-19 patients presented higher inflammatory cytokines and PGE-2 levels and CD14 + HLA-DRlow monocytes frequency than controls. Moreover, severe COVID-19 patients presented higher NF-κB p65 phosphorylation in CD14 + HLA-DRlow, as well as higher expression of TLR-4 and NF-κB p65 phosphorylation in CD14 + HLA-DRhigh compared to controls. The stimulation of LPS in whole blood of severe COVID-19 patients leads to lower cytokine production but higher PGE-2 levels compared to controls. Endotoxin challenge with both concentrations reduced the frequency of CD14 + HLA-DRlow in severe COVID-19 patients, but the increases in TLR-4 expression and NF-κB p65 phosphorylation were more pronounced in both CD14 + monocytes of healthy controls and mild COVID-19 patients compared to severe COVID-19 group. We conclude that acute SARS-CoV-2 infection is associated with diminished endotoxin response in monocytes. KEY MESSAGES: Severe COVID-19 patients had higher levels of LPS and systemic IL-6 and TNF-α. Severe COVID-19 patients presented higher CD14+HLA-DRlow monocytes. Increased TLR-4/NF-κB axis was identified in monocytes of severe COVID-19. Blunted production of cytokines after whole blood LPS stimulation in severe COVID-19. Lower TLR-4/NF-κB activation in monocytes after LPS stimulation in severe COVID-19.
Collapse
Affiliation(s)
- Gilson P Dorneles
- Laboratory of Cellular and Molecular Immunology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Rua Sarmento Leite, Porto Alegre, RS, 245, 90050-170, Brazil
- Graduate Program in Health Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | - Paula C Teixeira
- Laboratory of Cellular and Molecular Immunology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Rua Sarmento Leite, Porto Alegre, RS, 245, 90050-170, Brazil
- Graduate Program in Health Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | - Alessandra Peres
- Laboratory of Cellular and Molecular Immunology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Rua Sarmento Leite, Porto Alegre, RS, 245, 90050-170, Brazil
- Graduate Program in Biosciences, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | - Luiz Carlos Rodrigues Júnior
- Laboratory of Cellular and Molecular Immunology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Rua Sarmento Leite, Porto Alegre, RS, 245, 90050-170, Brazil
- Graduate Program in Biosciences, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | | | - Marta Chagas Monteiro
- Graduate Program in Pharmaceutical Science, Health Science Institute, Universidade Federal Do Pará, Belém, Pará, Brazil
| | - Sarah Eller
- Pharmacosciences Department, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | - Tiago F Oliveira
- Graduate Program in Health Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | - Eliana M Wendland
- Graduate Program in Health Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
- Graduate Program in Pediatrics, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | - Pedro R T Romão
- Laboratory of Cellular and Molecular Immunology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Rua Sarmento Leite, Porto Alegre, RS, 245, 90050-170, Brazil.
- Graduate Program in Health Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.
- Graduate Program in Biosciences, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.
| |
Collapse
|
|
21
|
Violi F, Nocella C. Editorial: Gut permeability-related endotoxemia and cardiovascular disease: A new clinical challenge. Front Cardiovasc Med 2023; 10:1118625. [PMID: 37025675 PMCID: PMC10071368 DOI: 10.3389/fcvm.2023.1118625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 03/09/2023] [Indexed: 04/08/2023] Open
Affiliation(s)
- Francesco Violi
- Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
- Mediterranea Cardiocentro-Napoli, Naples, Italy
- Correspondence: Francesco Violi
| | - Cristina Nocella
- Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| |
Collapse
|
|
22
|
Abstract
Systemic inflammation has been suggested to have a pivotal role in atherothrombosis, but the factors that trigger systemic inflammation have not been fully elucidated. Lipopolysaccharide (LPS) is a component of the membrane of Gram-negative bacteria present in the gut that can translocate into the systemic circulation, causing non-septic, low-grade endotoxaemia. Gut dysbiosis is a major determinant of low-grade endotoxaemia via dysfunction of the intestinal barrier scaffold, which is a prerequisite for LPS translocation into the systemic circulation. Experimental studies have demonstrated that LPS is present in atherosclerotic arteries but not in normal arteries. In atherosclerotic plaques, LPS promotes a pro-inflammatory status that can lead to plaque instability and thrombus formation. Low-grade endotoxaemia affects several cell types, including leukocytes, platelets and endothelial cells, leading to inflammation and clot formation. Low-grade endotoxaemia has been described in patients at risk of or with overt cardiovascular disease, in whom low-grade endotoxaemia was associated with atherosclerotic burden and its clinical sequelae. In this Review, we describe the mechanisms favouring the development of low-grade endotoxaemia, focusing on gut dysbiosis and changes in gut permeability; the plausible biological mechanisms linking low-grade endotoxaemia and atherothrombosis; the clinical studies suggesting that low-grade endotoxaemia is a risk factor for cardiovascular events; and the potential therapeutic tools to improve gut permeability and eventually eliminate low-grade endotoxaemia.
Collapse
|
|
23
|
TIRAP, TRAM, and Toll-Like Receptors: The Untold Story. Mediators Inflamm 2023; 2023:2899271. [PMID: 36926280 PMCID: PMC10014160 DOI: 10.1155/2023/2899271] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 01/30/2023] [Accepted: 02/06/2023] [Indexed: 03/09/2023] Open
Abstract
Toll-like receptors (TLRs) are the most studied receptors among the pattern recognition receptors (PRRs). They act as microbial sensors, playing major roles in the regulation of the innate immune system. TLRs mediate their cellular functions through the activation of MyD88-dependent or MyD88-independent signaling pathways. Myd88, or myeloid differentiation primary response 88, is a cytosolic adaptor protein essential for the induction of proinflammatory cytokines by all TLRs except TLR3. While the crucial role of Myd88 is well described, the contribution of other adaptors in mediating TLR signaling and function has been underestimated. In this review, we highlight important results demonstrating that TIRAP and TRAM adaptors are also required for full signaling activity and responses induced by most TLRs.
Collapse
|
|
24
|
dos Santos AAC, Rodrigues LE, Alecrim-Zeza AL, de Araújo Ferreira L, Trettel CDS, Gimenes GM, da Silva AF, Sousa-Filho CPB, Serdan TDA, Levada-Pires AC, Hatanaka E, Borges FT, de Barros MP, Cury-Boaventura MF, Bertolini GL, Cassolla P, Marzuca-Nassr GN, Vitzel KF, Pithon-Curi TC, Masi LN, Curi R, Gorjao R, Hirabara SM. Molecular and cellular mechanisms involved in tissue-specific metabolic modulation by SARS-CoV-2. Front Microbiol 2022; 13:1037467. [PMID: 36439786 PMCID: PMC9684198 DOI: 10.3389/fmicb.2022.1037467] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/26/2022] [Indexed: 09/09/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is triggered by the SARS-CoV-2, which is able to infect and cause dysfunction not only in lungs, but also in multiple organs, including central nervous system, skeletal muscle, kidneys, heart, liver, and intestine. Several metabolic disturbances are associated with cell damage or tissue injury, but the mechanisms involved are not yet fully elucidated. Some potential mechanisms involved in the COVID-19-induced tissue dysfunction are proposed, such as: (a) High expression and levels of proinflammatory cytokines, including TNF-α IL-6, IL-1β, INF-α and INF-β, increasing the systemic and tissue inflammatory state; (b) Induction of oxidative stress due to redox imbalance, resulting in cell injury or death induced by elevated production of reactive oxygen species; and (c) Deregulation of the renin-angiotensin-aldosterone system, exacerbating the inflammatory and oxidative stress responses. In this review, we discuss the main metabolic disturbances observed in different target tissues of SARS-CoV-2 and the potential mechanisms involved in these changes associated with the tissue dysfunction.
Collapse
Affiliation(s)
| | - Luiz Eduardo Rodrigues
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Amanda Lins Alecrim-Zeza
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Liliane de Araújo Ferreira
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Caio dos Santos Trettel
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Gabriela Mandú Gimenes
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Adelson Fernandes da Silva
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | | | - Tamires Duarte Afonso Serdan
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
- Department of Molecular Pathobiology, University of New York, New York, NY, United States
| | - Adriana Cristina Levada-Pires
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Elaine Hatanaka
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Fernanda Teixeira Borges
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
- Divisão de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Marcelo Paes de Barros
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Maria Fernanda Cury-Boaventura
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Gisele Lopes Bertolini
- Department of Physiological Sciences, Biological Science Center, State University of Londrina, Londrina, PR, Brazil
| | - Priscila Cassolla
- Department of Physiological Sciences, Biological Science Center, State University of Londrina, Londrina, PR, Brazil
| | | | - Kaio Fernando Vitzel
- School of Health Sciences, College of Health, Massey University, Auckland, New Zealand
| | - Tania Cristina Pithon-Curi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Laureane Nunes Masi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Rui Curi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
- Instituto Butantan, São Paulo, Brazil
| | - Renata Gorjao
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Sandro Massao Hirabara
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| |
Collapse
|
|
25
|
Hernández-Solis A, Güemes-González AM, Ruiz-Gómez X, Álvarez-Maldonado P, Castañeda-Casimiro J, Flores-López A, Ramírez-Guerra MA, Muñoz-Miranda O, Madera-Sandoval RL, Arriaga-Pizano LA, Nieto-Patlán A, Estrada-Parra S, Pérez-Tapia SM, Serafín-López J, Chacón-Salinas R, Escobar-Gutiérrez A, Soria-Castro R, Ruiz-Sánchez BP, Wong-Baeza I. IL-6, IL-10, sFas, granulysin and indicators of intestinal permeability as early biomarkers for a fatal outcome in COVID-19. Immunobiology 2022; 227:152288. [PMID: 36209721 PMCID: PMC9527226 DOI: 10.1016/j.imbio.2022.152288] [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: 07/14/2022] [Revised: 09/12/2022] [Accepted: 09/28/2022] [Indexed: 11/30/2022]
Abstract
The clinical presentation of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranges between mild respiratory symptoms and a severe disease that shares many of the features of sepsis. Sepsis is a deregulated response to infection that causes life-threatening organ failure. During sepsis, the intestinal epithelial cells are affected, causing an increase in intestinal permeability and allowing microbial translocation from the intestine to the circulation, which exacerbates the inflammatory response. Here we studied patients with moderate, severe and critical COVID-19 by measuring a panel of molecules representative of the innate and adaptive immune responses to SARS-CoV-2, which also reflect the presence of systemic inflammation and the state of the intestinal barrier. We found that non-surviving COVID-19 patients had higher levels of low-affinity anti-RBD IgA antibodies than surviving patients, which may be a response to increased microbial translocation. We identified sFas and granulysin, in addition to IL-6 and IL-10, as possible early biomarkers with high sensitivity (>73 %) and specificity (>51 %) to discriminate between surviving and non-surviving COVID-19 patients. Finally, we found that the microbial metabolite d-lactate and the tight junction regulator zonulin were increased in the serum of patients with severe COVID-19 and in COVID-19 patients with secondary infections, suggesting that increased intestinal permeability may be a source of secondary infections in these patients. COVID-19 patients with secondary infections had higher disease severity and mortality than patients without these infections, indicating that intestinal permeability markers could provide complementary information to the serum cytokines for the early identification of COVID-19 patients with a high risk of a fatal outcome.
Collapse
Affiliation(s)
- Alejandro Hernández-Solis
- Servicio de Neumología, Hospital General de México "Dr. Eduardo Liceaga", Secretaría de Salud, Mexico City, Mexico; Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Azmavet M Güemes-González
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Ximena Ruiz-Gómez
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Pablo Álvarez-Maldonado
- Servicio de Neumología, Hospital General de México "Dr. Eduardo Liceaga", Secretaría de Salud, Mexico City, Mexico
| | - Jessica Castañeda-Casimiro
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico; Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Argelia Flores-López
- Servicio de Neumología, Hospital General de México "Dr. Eduardo Liceaga", Secretaría de Salud, Mexico City, Mexico
| | - Martha Alicia Ramírez-Guerra
- Servicio de Neumología, Hospital General de México "Dr. Eduardo Liceaga", Secretaría de Salud, Mexico City, Mexico
| | - Omar Muñoz-Miranda
- Servicio de Neumología, Hospital General de México "Dr. Eduardo Liceaga", Secretaría de Salud, Mexico City, Mexico
| | - Ruth L Madera-Sandoval
- Unidad de Investigación Médica en Inmunoquímica, Centro Medico Nacional "Siglo XXI", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Lourdes A Arriaga-Pizano
- Unidad de Investigación Médica en Inmunoquímica, Centro Medico Nacional "Siglo XXI", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Alejandro Nieto-Patlán
- Departamento de Genética, Hospital Infantil de México Federico Gómez, Mexico City, Mexico; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Center for Human Immunobiology, Department of Allergy, Immunology and Rheumatology, Houston, TX, USA.
| | - Sergio Estrada-Parra
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Sonia Mayra Pérez-Tapia
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico; Unidad de Desarrollo e Investigación en Bioterapéuticos (UDIBI), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Mexico City, Mexico; Laboratorio Nacional para Servicios Especializados de Investigación, Desarrollo e Innovación (l+D+i) para Farmoquímicos y Biotecnológicos, LANSEIDI-FarBiotec-CONACyT. Mexico City, Mexico
| | - Jeanet Serafín-López
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Rommel Chacón-Salinas
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Alejandro Escobar-Gutiérrez
- Coordinación de Investigaciones Inmunológicas, Instituto de Diagnóstico y Referencia Epidemiológicos (InDRE), Secretaria de Salud, Mexico City, Mexico
| | - Rodolfo Soria-Castro
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Bibiana Patricia Ruiz-Sánchez
- Facultad de Medicina. Universidad Westhill, Mexico City, Mexico; Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Isabel Wong-Baeza
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico.
| |
Collapse
|
|
26
|
Palomino-Kobayashi LA, Ymaña B, Ruiz J, Mayanga-Herrera A, Ugarte-Gil MF, Pons MJ. Zonulin, a marker of gut permeability, is associated with mortality in a cohort of hospitalised peruvian COVID-19 patients. Front Cell Infect Microbiol 2022; 12:1000291. [PMID: 36147602 PMCID: PMC9485714 DOI: 10.3389/fcimb.2022.1000291] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 08/16/2022] [Indexed: 01/08/2023] Open
Abstract
Zonulin has previously been related to intestinal permeability in various inflammatory diseases, and more recently to the physiopathology of severe COVID-19 infections. We analysed serum samples from a previous study of a Peruvian cohort of hospitalised COVID-19 patients, for the quantification of zonulin by sandwich ELISA. Comparisons with clinical data, haematological and biochemical parameters and cytokine/chemokine levels were made. We found higher baseline zonulin levels in deceased patients, and zonulin was associated with fatal outcome in multivariable analyses, even after adjustment for age, gender, and obesity. There were also positive correlations between zonulin, creatinine, D-dimer values and prothrombin time, while inverse correlations were found for Sa/FiO2 ratio and CCL5 (RANTES). Further longitudinal studies are recommended to analyse the variation of zonulin levels over time as well as their relationship with long-COVID.
Collapse
Affiliation(s)
| | - Barbara Ymaña
- Grupo Enfermedades Infecciosas Emergentes. Universidad Científica del Sur, Lima, Peru
| | - Joaquim Ruiz
- Grupo Enfermedades Infecciosas Emergentes. Universidad Científica del Sur, Lima, Peru
| | - Ana Mayanga-Herrera
- Laboratorio de Cultivo Celular e Inmunología, Universidad Científica del Sur, Lima, Peru
| | - Manuel F. Ugarte-Gil
- Grupo Peruano de Estudio de Enfermedades Autoinmunes Sistémicas, Universidad Científica del Sur, Lima, Peru,Hospital Nacional Guillermo Almenara Irigoyen, EsSalud, Lima, Peru
| | - Maria J. Pons
- Grupo Enfermedades Infecciosas Emergentes. Universidad Científica del Sur, Lima, Peru,*Correspondence: Maria J. Pons,
| |
Collapse
|
|
27
|
Wais T, Hasan M, Rai V, Agrawal DK. Gut-brain communication in COVID-19: molecular mechanisms, mediators, biomarkers, and therapeutics. Expert Rev Clin Immunol 2022; 18:947-960. [PMID: 35868344 PMCID: PMC9388545 DOI: 10.1080/1744666x.2022.2105697] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 07/21/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Infection with COVID-19 results in acute respiratory symptoms followed by long COVID multi-organ effects presenting with neurological, cardiovascular, musculoskeletal, and gastrointestinal (GI) manifestations. Temporal relationship between gastrointestinal and neurological symptoms is unclear but warranted for exploring better clinical care for COVID-19 patients. AREAS COVERED We critically reviewed the temporal relationship between gut-brain axis after SARS-CoV-2 infection and the molecular mechanisms involved in neuroinvasion following GI infection. Mediators are identified that could serve as biomarkers and therapeutic targets in SARS-CoV-2. We discussed the potential therapeutic approaches to mitigate the effects of GI infection with SARS-CoV-2. EXPERT OPINION Altered gut microbiota cause increased expression of various mediators, including zonulin causing disruption of tight junction. This stimulates enteric nervous system and signals to CNS precipitating neurological sequalae. Published reports suggest potential role of cytokines, immune cells, B(0)AT1 (SLC6A19), ACE2, TMRSS2, TMPRSS4, IFN-γ, IL-17A, zonulin, and altered gut microbiome in gut-brain axis and associated neurological sequalae. Targeting these mediators and gut microbiome to improve immunity will be of therapeutic significance. In-depth research and well-designed large-scale population-based clinical trials with multidisciplinary and collaborative approaches are warranted. Investigating the temporal relationship between organs involved in long-term sequalae is critical due to evolving variants of SARS-CoV-2.
Collapse
Affiliation(s)
- Tameena Wais
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Mehde Hasan
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Vikrant Rai
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Devendra K. Agrawal
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| |
Collapse
|
|
28
|
Mesenchymal stem cells and their derived small extracellular vesicles for COVID-19 treatment. Stem Cell Res Ther 2022; 13:410. [PMID: 35962458 PMCID: PMC9372991 DOI: 10.1186/s13287-022-03034-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 07/14/2022] [Indexed: 11/24/2022] Open
Abstract
Since December 2019, the coronavirus (COVID-19) pandemic has imposed huge burdens to the whole world, seriously affecting global economic growth, and threatening people’s lives and health. At present, some therapeutic regimens are available for treatment of COVID-19 pneumonia, including antiviral therapy, immunity therapy, anticoagulant therapy, and others. Among them, injection of mesenchymal stem cells (MSCs) is currently a promising therapy. The preclinical studies and clinical trials using MSCs and small extracellular vesicles derived from MSCs (MSC-sEVs) in treating COVID-19 were summarized. Then, the molecular mechanism, feasibility, and safety of treating COVID-19 with MSCs and MSC-sEVs were also discussed.
Collapse
|
|
29
|
Rovito R, Augello M, Ben-Haim A, Bono V, d'Arminio Monforte A, Marchetti G. Hallmarks of Severe COVID-19 Pathogenesis: A Pas de Deux Between Viral and Host Factors. Front Immunol 2022; 13:912336. [PMID: 35757770 PMCID: PMC9231592 DOI: 10.3389/fimmu.2022.912336] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/02/2022] [Indexed: 12/15/2022] Open
Abstract
Two years into Coronavirus Disease 2019 (COVID-19) pandemic, a comprehensive characterization of the pathogenesis of severe and critical forms of COVID-19 is still missing. While a deep dysregulation of both the magnitude and functionality of innate and adaptive immune responses have been described in severe COVID-19, the mechanisms underlying such dysregulations are still a matter of scientific debate, in turn hampering the identification of new therapies and of subgroups of patients that would most benefit from individual clinical interventions. Here we review the current understanding of viral and host factors that contribute to immune dysregulation associated with COVID-19 severity in the attempt to unfold and broaden the comprehension of COVID-19 pathogenesis and to define correlates of protection to further inform strategies of targeted therapeutic interventions.
Collapse
Affiliation(s)
- Roberta Rovito
- Clinic of Infectious Diseases and Tropical Medicine, Azienda Socio Sanitaria Territoriale (ASST) Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
| | - Matteo Augello
- Clinic of Infectious Diseases and Tropical Medicine, Azienda Socio Sanitaria Territoriale (ASST) Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
| | - Assaf Ben-Haim
- Clinic of Infectious Diseases and Tropical Medicine, Azienda Socio Sanitaria Territoriale (ASST) Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
| | - Valeria Bono
- Clinic of Infectious Diseases and Tropical Medicine, Azienda Socio Sanitaria Territoriale (ASST) Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
| | - Antonella d'Arminio Monforte
- Clinic of Infectious Diseases and Tropical Medicine, Azienda Socio Sanitaria Territoriale (ASST) Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
| | - Giulia Marchetti
- Clinic of Infectious Diseases and Tropical Medicine, Azienda Socio Sanitaria Territoriale (ASST) Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
| |
Collapse
|
|
30
|
Vitkov L, Knopf J, Krunić J, Schauer C, Schoen J, Minnich B, Hannig M, Herrmann M. Periodontitis-Derived Dark-NETs in Severe Covid-19. Front Immunol 2022; 13:872695. [PMID: 35493525 PMCID: PMC9039207 DOI: 10.3389/fimmu.2022.872695] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/23/2022] [Indexed: 11/15/2022] Open
Abstract
The frequent severe COVID-19 course in patients with periodontitis suggests a link of the aetiopathogenesis of both diseases. The formation of intravascular neutrophil extracellular traps (NETs) is crucial to the pathogenesis of severe COVID-19. Periodontitis is characterised by an increased level of circulating NETs, a propensity for increased NET formation, delayed NET clearance and low-grade endotoxemia (LGE). The latter has an enormous impact on innate immunity and susceptibility to infection with SARS-CoV-2. LPS binds the SARS-CoV-2 spike protein and this complex, which is more active than unbound LPS, precipitates massive NET formation. Thus, circulating NET formation is the common denominator in both COVID-19 and periodontitis and other diseases with low-grade endotoxemia like diabetes, obesity and cardiovascular diseases (CVD) also increase the risk to develop severe COVID-19. Here we discuss the role of propensity for increased NET formation, DNase I deficiency and low-grade endotoxaemia in periodontitis as aggravating factors for the severe course of COVID-19 and possible strategies for the diminution of increased levels of circulating periodontitis-derived NETs in COVID-19 with periodontitis comorbidity.
Collapse
Affiliation(s)
- Ljubomir Vitkov
- Clinic of Operative Dentistry, Periodontology and Preventive Dentistry, Saarland University, Homburg, Germany.,Department of Environment & Biodiversity, University of Salzburg, Salzburg, Austria.,Department of Dental Pathology, University of East Sarajevo, East Sarajevo, Bosnia and Herzegovina
| | - Jasmin Knopf
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.,Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Jelena Krunić
- Department of Dental Pathology, University of East Sarajevo, East Sarajevo, Bosnia and Herzegovina
| | - Christine Schauer
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.,Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Janina Schoen
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.,Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Bernd Minnich
- Department of Environment & Biodiversity, University of Salzburg, Salzburg, Austria
| | - Matthias Hannig
- Clinic of Operative Dentistry, Periodontology and Preventive Dentistry, Saarland University, Homburg, Germany
| | - Martin Herrmann
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.,Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| |
Collapse
|
|
31
|
The Rationale and Current Status of Endotoxin Adsorption in the Treatment of Septic Shock. J Clin Med 2022; 11:jcm11030619. [PMID: 35160068 PMCID: PMC8836955 DOI: 10.3390/jcm11030619] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 02/05/2023] Open
Abstract
Lipopolysaccharide, the main component of the outer membrane of Gram-negative bacteria is a highly potent endotoxin responsible for organ dysfunction in sepsis. It is present in the blood stream not only in Gram-negative infections, but also in Gram-positive and fungal infections, presumably due to sepsis-related disruption of the intestinal barrier. Various pathways, both extra- and intracellular, are involved in sensing endotoxin and non-canonical activation of caspase-mediated pyroptosis is considered to have a major role in sepsis pathophysiology. Endotoxin induces specific pathological alterations in several organs, which contributes to poor outcomes. The adverse consequences of endotoxin in the circulation support the use of anti-endotoxin therapies, yet more than 30 years of experience with endotoxin adsorption therapies have not provided clear evidence in favor of this treatment modality. The results of small studies support timely endotoxin removal guided by measuring the levels of endotoxin; unfortunately, this has not been proven in large, randomized studies. The presence of endotoxemia can be demonstrated in the majority of patients with COVID-19, yet only case reports and case series describing the effects of endotoxin removal in these patients have been published to date. The place of blood purification therapies in the treatment of septic shock has not yet been determined.
Collapse
|
|
32
|
Violi F, Pignatelli P, Oliva A, Cammisotto V. Reply to Chen and Vitetta. Clin Transl Gastroenterol 2022; 13:e00448. [PMID: 35029168 PMCID: PMC8806381 DOI: 10.14309/ctg.0000000000000448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Affiliation(s)
- Francesco Violi
- Sapienza University of Rome and Mediterranea Cardiocentro, Naples, Italy
| | - Pasquale Pignatelli
- Sapienza University of Rome and Mediterranea Cardiocentro, Naples, Italy
- Department of Clinical Internal, Anesthesiological, and Cardiovascular Sciences, Sapienza University of Rome, Itlaly
| | - Alessandra Oliva
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Vittoria Cammisotto
- Department of General Surgery and Surgical Speciality Paride Stefanini, Sapienza University of Rome, Italy.
| |
Collapse
|
|
33
|
Chen J, Vitetta L. Gut Dysbiosis Could Be a Major Factor for the Effects of Low-Grade Endotoxemia in COVID-19 Comment on: Low-Grade Endotoxemia and Thrombosis in COVID-19. Clin Transl Gastroenterol 2022; 13:e00440. [PMID: 35080510 PMCID: PMC8806357 DOI: 10.14309/ctg.0000000000000440] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Affiliation(s)
- Jiezhong Chen
- Research Department, Medlab Clinical, Sydney, Australia;
| | - Luis Vitetta
- Research Department, Medlab Clinical, Sydney, Australia;
- The University of Sydney, Faculty of Medicine and Health, Sydney, Australia.
| |
Collapse
|
|
34
|
Mazzaccaro D, Giannetta M, Fancoli F, Milani V, Modafferi A, Malacrida G, Righini P, Marrocco-Trischitta MM, Nano G. COVID and venous thrombosis: systematic review of literature. THE JOURNAL OF CARDIOVASCULAR SURGERY 2021; 62:548-557. [PMID: 34520137 DOI: 10.23736/s0021-9509.21.12022-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
INTRODUCTION We aimed to review the prevalence, the risk factors and the outcomes of venous thrombosis (VT) in patients hospitalized for COronaVirus Disease 19 (COVID-19). METHODS Electronic bibliographic databases were searched using the words "COVID venous thrombosis". The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards. RESULTS The search of the Literature retrieved 877 results. After assessment of full texts, 69 papers were included in the qualitative analysis and 23 of them in the quantitative evaluation. The analyzed studies included a total of 106838 patients hospitalized for COVID-19 from 01/2020 to 12/2020. The pooled reported prevalence rate of VT was in median 16.7% (IQR 5.8%-30%), being higher in ICU patients (60.8%-85.4%). VT events were reported in about 75% of cases in the popliteal and calf veins. Signs and symptoms were present in 6.1% of cases. At quantitative evaluation, older age, D-dimer and obesity increased the odds to experience a VT (OR 3.54, 95%CI 0.65-6.43, P=0.01; OR=956.86, 95%CI 225.67-1668.05, P=0.01; OR 1.42, 95%CI 1.01-1.99, P=0.03 respectively). Female sex seemed to be protective against the odds of VT (OR 0.77, 95%CI 0.63-0.93, P=0.007). CONCLUSIONS Among patients hospitalized for COVID-19, VT is a relatively common finding, with higher prevalence rates in ICU patients. VT occurs mostly in the distal regions of the lower limb and is asymptomatic in most cases. Older age, obesity and higher D-dimer values on admission increased the odds of VT, while female sex was protective against the odds of VT.
Collapse
Affiliation(s)
- Daniela Mazzaccaro
- Operative Unit of Vascular Surgery, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy -
| | - Matteo Giannetta
- Operative Unit of Vascular Surgery, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Fabiana Fancoli
- Operative Unit of Vascular Surgery, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Valentina Milani
- Scientific Directorate, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Alfredo Modafferi
- Operative Unit of Vascular Surgery, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Giovanni Malacrida
- Operative Unit of Vascular Surgery, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Paolo Righini
- Operative Unit of Vascular Surgery, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | | | - Giovanni Nano
- Operative Unit of Vascular Surgery, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.,Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| |
Collapse
|
|
35
|
Oliva A, Rando E, Al Ismail D, De Angelis M, Cancelli F, Miele MC, Aronica R, Mauro V, Di Timoteo F, Loffredo L, Mastroianni CM. Role of Serum E-Selectin as a Biomarker of Infection Severity in Coronavirus Disease 2019. J Clin Med 2021; 10:4018. [PMID: 34501466 PMCID: PMC8432564 DOI: 10.3390/jcm10174018] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/26/2022] Open
Abstract
INTRODUCTION E-selectin is a recognized marker of endothelial activation; however, its place in Coronavirus Disease 2019 (COVID-19) has not been fully explored. Aims of the study are to compare sE-selectin values among the Intensive Care Unit (ICU)-admitted and non-admitted, survived and non-survived patients and those with or without thrombosis. METHODS A single-center study of patients with COVID-19 hospitalized at Policlinico Umberto I (Rome) from March to May 2020 was performed. Simple and multiple logistic regression models were developed. RESULTS One hundred patients were included, with a median age (IQR) of 65 years (58-78). Twenty-nine (29%) were admitted to ICU, twenty-eight (28%) died and nineteen (19%) had a thrombotic event. The median value (IQR) of sE-selectin was 26.1 ng/mL (18.1-35). sE-selectin values did not differ between deceased and survivors (p = 0.06) and among patients with or without a thrombotic event (p = 0.22). Compared with patients who did not receive ICU treatments, patients requiring ICU care had higher levels of sE-selectin (36.6 vs. 24.1 ng/mL; p < 0.001). In the multiple logistic regression model, sE-selectin levels > 33 ng/mL, PaO2/FiO2 < 200 and PaO2/FiO2 200-300 were significantly associated with an increased risk of ICU admission. sE-selectin values significantly correlated with a neutrophil count (R = 0.32 (p = 0.001)) and the number of days from the symptoms onset to hospitalization (R = 0.28 (p = 0.004)). CONCLUSIONS sE-selectin levels are predictive of ICU admission in COVID-19 patients. Since data on the relation between sE-selectin and COVID-19 are scarce, this study aims to contribute toward the comprehension of the pathogenic aspects of COVID-19 disease, giving a possible clinical marker able to predict its severity.
Collapse
Affiliation(s)
- Alessandra Oliva
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (E.R.); (D.A.I.); (M.D.A.); (F.C.); (M.C.M.); (R.A.); (V.M.); (F.D.T.); (C.M.M.)
| | - Emanuele Rando
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (E.R.); (D.A.I.); (M.D.A.); (F.C.); (M.C.M.); (R.A.); (V.M.); (F.D.T.); (C.M.M.)
- Sapienza School for Advanced Studies (SSAS), Sapienza University of Rome, Viale Regina Elena, 291, 00161 Rome, Italy
| | - Dania Al Ismail
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (E.R.); (D.A.I.); (M.D.A.); (F.C.); (M.C.M.); (R.A.); (V.M.); (F.D.T.); (C.M.M.)
| | - Massimiliano De Angelis
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (E.R.); (D.A.I.); (M.D.A.); (F.C.); (M.C.M.); (R.A.); (V.M.); (F.D.T.); (C.M.M.)
| | - Francesca Cancelli
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (E.R.); (D.A.I.); (M.D.A.); (F.C.); (M.C.M.); (R.A.); (V.M.); (F.D.T.); (C.M.M.)
| | - Maria Claudia Miele
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (E.R.); (D.A.I.); (M.D.A.); (F.C.); (M.C.M.); (R.A.); (V.M.); (F.D.T.); (C.M.M.)
| | - Raissa Aronica
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (E.R.); (D.A.I.); (M.D.A.); (F.C.); (M.C.M.); (R.A.); (V.M.); (F.D.T.); (C.M.M.)
| | - Vera Mauro
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (E.R.); (D.A.I.); (M.D.A.); (F.C.); (M.C.M.); (R.A.); (V.M.); (F.D.T.); (C.M.M.)
| | - Federica Di Timoteo
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (E.R.); (D.A.I.); (M.D.A.); (F.C.); (M.C.M.); (R.A.); (V.M.); (F.D.T.); (C.M.M.)
| | - Lorenzo Loffredo
- Department of Clinical, Internal Medicine, Anaesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy;
| | - Claudio M. Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (E.R.); (D.A.I.); (M.D.A.); (F.C.); (M.C.M.); (R.A.); (V.M.); (F.D.T.); (C.M.M.)
| |
Collapse
|
|
36
|
Oliva A, Miele MC, Di Timoteo F, De Angelis M, Mauro V, Aronica R, Al Ismail D, Ceccarelli G, Pinacchio C, d'Ettorre G, Mascellino MT, Mastroianni CM. Persistent Systemic Microbial Translocation and Intestinal Damage During Coronavirus Disease-19. Front Immunol 2021; 12:708149. [PMID: 34335624 PMCID: PMC8316921 DOI: 10.3389/fimmu.2021.708149] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 06/28/2021] [Indexed: 12/24/2022] Open
Abstract
Microbial translocation (MT) and intestinal damage (ID) are poorly explored in COVID-19. Aims were to assess whether alteration of gut permeability and cell integrity characterize COVID-19 patients, whether it is more pronounced in severe infections and whether it influences the development of subsequent bloodstream infection (BSI). Furthermore, we looked at the potential predictive role of TM and ID markers on Intensive Care Unit (ICU) admission and in-hospital mortality. Over March–July 2020, 45 COVID-19 patients were enrolled. Markers of MT [LPB (Lipopolysacharide Binding Protein) and EndoCab IgM] and ID [I-FABP (Intestinal Fatty Acid Binding Protein)] were evaluated at COVID-19 diagnosis and after 7 days. As a control group, age- and gender-matched healthy donors (HDs) enrolled during the same study period were included. Median age was 66 (56-71) years. Twenty-one (46.6%) were admitted to ICU and mortality was 22% (10/45). Compared to HD, a high degree of MT and ID was observed. ICU patients had higher levels of MT, but not of ID, than non-ICU ones. Likewise, patients with BSI had lower EndoCab IgM than non-BSI. Interestingly, patients with high degree of MT and low ID were likely to be admitted to ICU (AUC 0.822). Patients with COVID-19 exhibited high level of MT, especially subjects admitted to ICU. COVID-19 is associated with gut permeability.
Collapse
Affiliation(s)
- Alessandra Oliva
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Maria Claudia Miele
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Federica Di Timoteo
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Massimiliano De Angelis
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Vera Mauro
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Raissa Aronica
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Dania Al Ismail
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Giancarlo Ceccarelli
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Claudia Pinacchio
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Gabriella d'Ettorre
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Maria Teresa Mascellino
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Claudio M Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| |
Collapse
|
|
37
|
Alpers DH. Is the Intestine a Portal of Entry for the Serious COVID-19 Complications of Endotoxemia and Thrombosis? Clin Transl Gastroenterol 2021; 12:e00367. [PMID: 34092778 PMCID: PMC8183696 DOI: 10.14309/ctg.0000000000000367] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 04/28/2021] [Indexed: 01/12/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 infection has been associated with both endotoxemia and thrombosis of small and large vessels, but the relationship between these 2 phenomena has not been pursued. Oliva et al. in this issue of Clinical and Translational Gastroenterology demonstrate an association between the 2 findings and suggest that increased intestinal permeability is a possible mechanism to explain the endotoxemia. Although the evidence to support this hypothesis is only suggestive, the role of the small intestine in the illness produced by the virus needs to be further explored.
Collapse
Affiliation(s)
- David H Alpers
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| |
Collapse
|