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Li Z, Jiang S, Liu W, Yang X, Liu F, Li X, Li J, Yu M, Wei Z, Wang B, Qian D. A promising endeavor against human cytomegalovirus: Predominant epitopes-based recombinant subunit vaccine RH EcIE1/pp65/pp150. Virulence 2025; 16:2497903. [PMID: 40277436 PMCID: PMC12064061 DOI: 10.1080/21505594.2025.2497903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 12/23/2024] [Accepted: 04/21/2025] [Indexed: 04/26/2025] Open
Abstract
Human cytomegalovirus (HCMV) is widespread in the population, typically remaining latent. However, it can cause severe morbidity and mortality in transplant patients and immunodeficient individuals. Currently, there is no approved vaccine against HCMV. This study used immunoinformatics methods to predict the predominant T and B-cell epitopes of three key HCMV proteins, including phosphoprotein 65 (pp65), pp150, and immediate-early protein 1 (IE1). Subsequently, we synthesized a recombinant subunit vaccine (RHEcIE1/pp65/pp150) from Escherichia coli, comprising RHEc-1 and RHEc-2. We observed that the RHEcIE1/pp65/pp150 vaccine exhibited high safety and immunogenicity in mice, enhancing a significant upregulation of CD80, CD86, CD40, and MHCII on dendritic cells and macrophages. Additionally, the vaccine activated innate immune responses through the NF-κB signalling pathway, triggering CD4+ and CD8+T cells to secrete tumour necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-2, directing the T-cell response towards Th1. Moreover, it stimulated CD4+T cells to secrete IL-4, IL-6, and IL-10, promoting B-cell immunity. Furthermore, the RHEcIE1/pp65/pp150 vaccine induced the formation of abundant memory cells and high levels of neutralizing antibody titres, conducive to providing long-lasting protection. Taken together, the RHEcIE1/pp65/pp150 vaccine is a promising endeavour against HCMV, and these findings contribute valuable insights to the development of HCMV vaccine candidates.
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MESH Headings
- Cytomegalovirus Vaccines/immunology
- Cytomegalovirus Vaccines/genetics
- Cytomegalovirus Vaccines/administration & dosage
- Animals
- Vaccines, Subunit/immunology
- Vaccines, Subunit/genetics
- Vaccines, Subunit/administration & dosage
- Cytomegalovirus/immunology
- Cytomegalovirus/genetics
- Mice
- Viral Matrix Proteins/immunology
- Viral Matrix Proteins/genetics
- Cytomegalovirus Infections/prevention & control
- Cytomegalovirus Infections/immunology
- Humans
- Vaccines, Synthetic/immunology
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/genetics
- Phosphoproteins/immunology
- Phosphoproteins/genetics
- Epitopes, T-Lymphocyte/immunology
- Epitopes, T-Lymphocyte/genetics
- Epitopes, B-Lymphocyte/immunology
- Epitopes, B-Lymphocyte/genetics
- Female
- Immediate-Early Proteins/immunology
- Immediate-Early Proteins/genetics
- Antibodies, Viral/blood
- Mice, Inbred BALB C
- Immunogenicity, Vaccine
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Affiliation(s)
- Zonghui Li
- Department of Pathogenic Biology, Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Clinical Laboratory, Chengdu Aerotropolis Asia Heart Hospital, Chengdu, China
| | - Shasha Jiang
- Department of Pathogenic Biology, Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Wenxuan Liu
- Department of Pathogenic Biology, Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xiaoli Yang
- Department of Pathogenic Biology, Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Fengjun Liu
- Department of Pathogenic Biology, Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xu Li
- Department of Pathogenic Biology, Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Jun Li
- Department of Pathogenic Biology, Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Meng Yu
- Department of Pathogenic Biology, Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Zhun Wei
- Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, China
| | - Bin Wang
- Department of Pathogenic Biology, Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Dongmeng Qian
- Department of Pathogenic Biology, Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China
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Hidaka S, Tanabe K, Kobayashi S. Incidence of cytomegalovirus infection after kidney transplantation in the modern era of immunosuppression: the VINTAGE study. Ren Fail 2025; 47:2491658. [PMID: 40260519 PMCID: PMC12016247 DOI: 10.1080/0886022x.2025.2491658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 04/01/2025] [Accepted: 04/03/2025] [Indexed: 04/23/2025] Open
Abstract
Cytomegalovirus (CMV) infection is a frequent complication following kidney transplantation that affects transplant outcomes. This study aimed to (i) estimate the 12-month cumulative incidence of CMV antigenemia (AG) in adult kidney transplant recipients not receiving antiviral prophylaxis, (ii) identify the risk factors for CMV AG, and (iii) assess the impact of CMV AG on transplant outcomes. This study included 128 living donor kidney recipients (aged ≥20 years) who underwent transplantation between 2012 and 2020. The mean recipient age was 52.8 ± 13.0 years. The overall positive CMV AG rates were 10.9%, 35.9%, 45.3%, 53.1%, and 59.4% (95% confidence interval (CI), 50.9-67.9) at 1, 2, 3, 6, and 12 months posttransplantation, respectively. The 12-month incidence rates in D-/R-, D-/R+, D+/R+, and D+/R - were 0%, 25.0%, 62.2%, and 81.3%, respectively. Multivariable analysis revealed that the risk of CMV AG increased with a stepwise increase in CMV serostatus risk category (hazard ratio (HR), 2.65; 95% CI, 1.66-4.21; p < .001) and recipient age (HR, 1.37 per 10-year increase; 95% CI, 1.14-1.65; p < .001). Positive CMV AG was associated with an increased risk of antibody-mediated rejection (HR, 21.40; 95% CI, 2.59-176.2; p = .005) and lower estimated glomerular filtration rate (p = .026). The risk of CMV AG is highest within the first 3 months posttransplant and persists for approximately 7-8 months in D + recipients. These findings underscore the importance of regular CMV monitoring for at least 6 months posttransplantation, particularly in centers employing preemptive therapy.
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Affiliation(s)
- Sumi Hidaka
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Kazunari Tanabe
- Kidney Transplant and Robotic Surgery Center, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Shuzo Kobayashi
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kanagawa, Japan
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3
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Beyer AP, Moise PA, Wong M, Gao W, Xiang C, Shen P, Pavlakis M, Vincenti F, Wang W. Clinical events and healthcare resource utilization associated with neutropenia and leukopenia among adult kidney transplant recipients receiving valganciclovir. World J Transplant 2025; 15:102671. [DOI: 10.5500/wjt.v15.i2.102671] [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: 10/24/2024] [Revised: 12/09/2024] [Accepted: 01/23/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) prophylaxis with valganciclovir and ganciclovir is associated with elevated neutropenia and leukopenia risk in kidney transplant recipients, although the impact of these events on healthcare resource utilization (HCRU) and clinical outcomes is unclear.
AIM To quantify clinical events and HCRU associated with neutropenia and leukopenia among adults receiving valganciclovir and/or ganciclovir post-kidney transplantation.
METHODS Adult kidney transplant recipients receiving valganciclovir and/or ganciclovir prophylaxis were identified in the TriNetX database from 2012 to 2021. Patient characteristics were evaluated in the 1-year period pre-first transplant. HCRU and adjusted event rates per person-year were evaluated in follow-up year 1 and years 2-5 after first kidney transplantation among cohorts with vs without neutropenia and/or leukopenia.
RESULTS Of 15398 identified patients, the average age was 52.39 years and 58.70% were male. Patients with neutropenia and/or leukopenia had greater risk of clinical events for CMV-related events, opportunistic infections, use of granulocyte colony stimulating factor, and hospitalizations (relative risk > 1 in year 1 and years 2-5). Patients with vs without neutropenia and/or leukopenia had higher HCRU in year 1 and years 2-5 post kidney transplantation, including the mean number of inpatient admissions (year 1: 3.47 vs 2.76; years 2-5: 2.70 vs 2.29) and outpatient visits (48.97 vs 34.42; 31.73 vs 15.59, respectively), as well as the mean number of labs (1654.55 vs 1182.27; 622.37 vs 327.89).
CONCLUSION Adults receiving valganciclovir and/or ganciclovir prophylaxis post-kidney transplantation had greater risk of neutropenia and/or leukopenia, which were associated with higher clinical event rates and HCRU up to 5 years post-transplantation. These findings suggest the need for alternative prophylaxis options with lower myelosuppressive effects to improve patient outcomes.
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Affiliation(s)
- Andrew P Beyer
- Department of Value and Implementation Outcomes Research, Merck & Co., Inc., Rahway, NJ 07065, United States
| | - Pamela A Moise
- Medical Affairs, Merck & Co., Inc., Rahway, NJ 07065, United States
| | - Michael Wong
- Scientific Affairs, Merck & Co., Inc., Rahway, NJ 07065, United States
| | - Wei Gao
- Analysis Group, Boston, MA 02199, United States
| | | | | | - Martha Pavlakis
- The Transplant Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
| | - Flavio Vincenti
- The Transplant Services, University of California San Francisco, San Francisco, CA 94143, United States
| | - Weijia Wang
- Department of Value and Implementation Outcomes Research, Merck & Co., Inc., Rahway, NJ 07065, United States
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Diaz-Decaro J, Demmler-Harrison GJ, Marden JR, Anderson A, Basnet S, Gaburo K, Kirson N, Desai U, Buck PO. Epidemiology and Economic Burden of Diagnosed Congenital Cytomegalovirus Infection in the First 2 Years of Life among Commercially Insured and Medicaid-Insured Individuals in the United States. Clin Ther 2025; 47:426-435. [PMID: 40204615 DOI: 10.1016/j.clinthera.2025.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 01/29/2025] [Accepted: 03/10/2025] [Indexed: 04/11/2025]
Abstract
PURPOSE Congenital cytomegalovirus (cCMV) is the leading infectious cause of congenital birth defects. Although approximately 20% to 25% of infants born with cCMV develop long-term health complications such as sensorineural hearing loss, developmental issues, and microcephaly, studies on the disease burden of cCMV are limited. In this study, we assessed the epidemiology, economic burden, and disease burden of clinically diagnosed cCMV in the United States using insurance claims data. METHODS This retrospective study utilized Merative MarketScan Commercial Claims and Encounters and Multi-State Medicaid data from 2010 to 2019. Annual prevalence of clinically diagnosed cCMV at birth was estimated separately for each payer population. To assess economic burden, infants whose first cCMV diagnosis (index date) was within 1 month of birth were included in the cCMV cohort and matched to infants without cCMV infection for whom an index date was selected at random from all medical claims within 1 month of birth. Cohorts were matched 1:1 on demographics, insurance type, birth, and index years. All infants were required to have ≥2 years of continuous enrollment with prescription drug coverage after the index date (study period). Health care resource use and costs in 2021 USD ($) were summarized separately for the first and second years of the study period. Costs for birth admissions were also described. FINDINGS The prevalence of clinically diagnosed cCMV at birth peaked in 2018 at 18.43 and 34.37 per 100,000 in the commercial and Medicaid populations, respectively. One hundred eighteen commercially insured (mean age at index date, 0.3 months; 46.6% female) and 351 Medicaid-insured matched pairs (mean age at index date, 0.2 months; 43.6% female) were included in the economic burden analyses. Mean (median) birth admission costs for commercially and Medicaid-insured infants with clinically diagnosed cCMV were $195,630 ($22,896; vs $24,195 [$3105]) and $57,182 ($9807; vs $5732 [$1566]), respectively. Additionally, excess costs due to cCMV in years 1 and 2 were $9427 ($5089) and $15,901 ($1573) for commercially insured, and $11,104 ($1446) and $12,205 ($721) for Medicaid-insured, respectively. Among potential cCMV sequelae, infants in the cCMV cohort experienced higher rates of hearing loss and developmental/motor delays during the first 2 years. IMPLICATIONS Diagnosed prevalence of cCMV at birth increased over time from 2010 to 2018. Infants with clinically diagnosed cCMV have costlier birth admissions and substantial disease burden in the first 2 years of life. These results emphasize the need for primary prevention methods, such as vaccination, to decrease the burden of cCMV.
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Affiliation(s)
| | - Gail J Demmler-Harrison
- Baylor College of Medicine, Pediatric Infectious Disease, Texas Children's Hospital, Houston, Texas
| | | | | | | | | | | | - Urvi Desai
- Analysis Group, Inc, Boston, Massachusetts
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5
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Lynch K, Märtson AG. The Importance of Drug Exposure in the Development of Cytomegalovirus Resistance. Int J Antimicrob Agents 2025:107537. [PMID: 40374080 DOI: 10.1016/j.ijantimicag.2025.107537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 04/28/2025] [Accepted: 05/04/2025] [Indexed: 05/17/2025]
Abstract
Human cytomegalovirus (CMV) is a widespread pathogen which remains asymptomatic in healthy individuals. However, CMV disease can be life-threatening in immunocompromised individuals, particularly in transplant patients. This disease is routinely managed by antiviral agents including (val)ganciclovir, foscarnet, cidofovir, letermovir, and maribavir. Subtherapeutic antiviral drug exposure is a common occurrence and can lead to drug-resistant CMV development, a key contributor to disease progression. Breakthrough CMV often results in graft loss, end-organ failure, or death. By optimising intracellular exposure levels of antiviral therapies, it may be possible to improve patient outcomes. Therefore, this review aims to explore the relationship between antiviral exposure and the development of drug-resistant CMV. There are several challenges to achieving optimal concentrations of current and novel CMV therapies. Narrow therapeutic indices and toxicity profiles of current CMV therapeutics contribute to their subtherapeutic exposure and hence suboptimal clinical outcomes. Alternately, novel antivirals such as letermovir and maribavir offer improved pharmacokinetic profiles. However, these agents are associated with rapid resistance development. Overall, a distinct gap exists in understanding the relationship between antiviral exposure and resistance development. As a result, current clinical markers used to predict clinical efficacy lack reliability. In future, resistance development in relation to drug exposure should be included as a clinical trial endpoint to gain understanding of exposure-resistance relationships. With solid knowledge of these relationships, more predictive in vitro and in vivo markers of clinical efficacy can be identified. Additionally, pharmacokinetic-pharmacodynamic models and combination therapies should be further explored in to improve the management of CMV.
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Affiliation(s)
- Katie Lynch
- Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, The Netherlands
| | - Anne-Grete Märtson
- Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, The Netherlands.
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6
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Alhalabi M, Alshiekh HA, Alsaiad S, Zarzar M. Prevalence of opportunistic infections in Syrian inflammatory bowel disease patients on biologic therapy: a multi-center retrospective cross-sectional study. BMC Infect Dis 2025; 25:652. [PMID: 40320559 PMCID: PMC12051298 DOI: 10.1186/s12879-025-11063-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/30/2025] [Indexed: 05/08/2025] Open
Abstract
BACKGROUND Hepatitis B, hepatitis C, cytomegalovirus (CMV), and tuberculosis (TB) pose significant risks to patients with inflammatory bowel disease (IBD) receiving biological therapy. However, data on the prevalence of these infections in Syria are scarce. METHODS We conducted a retrospective chart review of IBD patients receiving biologic therapy at Damascus Hospital and Ibn Al-Nafees Hospital, two major public institutions in Syria, between January 2021 and November 2024. A minimum sample size of 130 was estimated; however, all available records were reviewed. RESULTS Among 185 IBD patients (104 from Damascus and 81 from Ibn Al-Nafees), 51.4% had ulcerative colitis and 47.6% had Crohn's disease. The smoking prevalence was 9.2%, which was higher in Crohn's disease (5.9%) than in ulcerative colitis (3.2%). TST performed in 61.1% of patients, with 4.3% positivity, and interferon-gamma release assay (IGRA) in 8.7% (1.1% positive). Hepatitis B surface antigen (HBsAg) and anti-HBc antibodies were found in 2.7% and 5.4% of the patients, respectively, while hepatitis C seroprevalence was low (0.5%). CMV seropositivity was high in Damascus (50.8%), with two cases (1.1%) of CMV colitis. Biologic therapies included infliximab (42.7%), ustekinumab (24.3%), golimumab (10.8%), and adalimumab (6.5%). Data gaps, particularly in viral serology and TB screening, are notable. CONCLUSION This study identifies deficiencies in TB/hepatitis B screening (notably anti-HBs Ab) and elevated CMV seroprevalence among Syrian IBD patients receiving biologics, extending to immunosuppressed cohorts (rheumatology, dermatology, oncology). Insufficient screening heightens occult infection/reactivation risks, necessitating standardized pretreatment protocols to reduce morbidity in high-risk populations. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Marouf Alhalabi
- Gastroenterologist at Gastroenterology Department of Damascus Hospital, Almujtahed Street, Damascus, Syria.
| | | | - Shadi Alsaiad
- Gastroenterologist at Gastroenterology Department of Damascus Hospital, Almujtahed Street, Damascus, Syria
| | - Mouayad Zarzar
- Gastroenterologist at Gastroenterology Department of Damascus Hospital, Almujtahed Street, Damascus, Syria
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7
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Ware M, Motekalem Y, Zaslavsky K, Cruz-Pimentel M, Kukreti V, Kaplan AJ, Yan P. CMV-Related Hemorrhagic Retinal Vasculitis in a Multiple Myeloma Patient on Daratumumab Therapy: A Case Report. Ocul Immunol Inflamm 2025; 33:701-704. [PMID: 39586070 DOI: 10.1080/09273948.2024.2432554] [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: 04/18/2024] [Revised: 11/04/2024] [Accepted: 11/12/2024] [Indexed: 11/27/2024]
Abstract
PURPOSE To report a case of cytomegalovirus (CMV)-related hemorrhagic retinal vasculitis in a patient with multiple myeloma (MM) on daratumumab, a trial cereblon E3 ligase modulatory drug (CELMoD), dexamethasone, and acyclovir, and discuss clinical implications for CMV prophylaxis. METHODS Case report, narrative review of CMV reactivation risk in MM patients on daratumumab and antiviral agent efficacy for CMV prophylaxis. RESULTS A 63-year-old female presented with 3 days of progressive unilateral vision loss in the right eye to the level of counting fingers. She had a history of relapsed and refractory MM and autologous stem cell transplant (ASCT). At the time of presentation, she was receiving daratumumab, a trial CELMoD, dexamethasone, and acyclovir. Posterior segment exam demonstrated trace vitreous cells (0.5+ vitritis as per SUN criteria) and scattered hemorrhages with multifocal intraluminal vascular whitening, aligned with infectious posterior uveitis and suggestive of panretinal occlusive vasculitis. Optical coherence tomography showed inner macular edema and epiretinal membrane formation. CMV reactivation was confirmed with PCR of anterior chamber fluid and blood. CONCLUSION Patients with MM on daratumumab are at increased risk of opportunistic reactivations including CMV, potentially due to daratumumab's immunomodulatory side effects. Our patient developed CMV-related hemorrhagic retinal vasculitis despite low-dose acyclovir, which provides limited protection against CMV reactivation in CMV seropositive individuals. This case report therefore offers casuistic support for ophthalmic screening for CMV reactivation or CMV prophylaxis with letermovir in this patient population.
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Affiliation(s)
- Matthaeus Ware
- Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yasmin Motekalem
- Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kirill Zaslavsky
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Miguel Cruz-Pimentel
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
- Department of Paediatric Ophthalmology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Vishal Kukreti
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Alexander J Kaplan
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
- Department of Ophthalmology and Vision Sciences, Kensington Vision and Research Centre, Toronto, Ontario, Canada
| | - Peng Yan
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
- Department of Ophthalmology and Vision Sciences, Kensington Vision and Research Centre, Toronto, Ontario, Canada
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Kang S. Tissue-invasive upper gastrointestinal cytomegalovirus disease in transplant and non-transplant patients. Korean J Intern Med 2025; 40:343-344. [PMID: 40360216 PMCID: PMC12081113 DOI: 10.3904/kjim.2025.096] [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] [Received: 03/23/2025] [Accepted: 04/02/2025] [Indexed: 05/15/2025] Open
Affiliation(s)
- Seokin Kang
- Division of Gastroenterology, Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
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9
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Blanco R, Muñoz JP. Porphyromonas gingivalis and Human Cytomegalovirus Co-Infection: A Potential Link Between Periodontal Disease and Oral Cancer Development. Cancers (Basel) 2025; 17:1525. [PMID: 40361452 PMCID: PMC12071019 DOI: 10.3390/cancers17091525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2025] [Revised: 04/21/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
Periodontal disease (PD) is an inflammatory condition that can contribute to the development of oral cancer. Chronic inflammation from PD can lead to the release of inflammatory mediators and growth factors that promote tumorigenesis. Porphyromonas gingivalis (P. gingivalis) is one of several pathogens implicated in PD and its potential link to oral cancer. However, other viral infections, such as human cytomegalovirus (HCMV), can also contribute to chronic inflammation, creating a favorable environment for oral cancer development. OBJECTIVES The present literature review tries to investigate the possible influence of P. gingivalis and HCMV co-infection in fostering the development of oral cancer and chronic periodontitis. METHODS A comprehensive search was conducted in PubMed and Google Scholar, focusing on the relevance and significance of articles that examine the role of P. gingivalis and HCMV in periodontal disease and oral cancer. RESULTS The evidence suggests that P. gingivalis and HCMV may act synergistically to modulate host immunity, disrupt epithelial integrity, and interfere with key cellular pathways. These interactions may enhance tissue destruction and foster a microenvironment conducive to malignant transformation. However, most of these findings stem from in vitro models and small-scale clinical studies, limiting the generalizability and clinical relevance of current conclusions. CONCLUSIONS Although the proposed interaction between P. gingivalis and HCMV provides a compelling framework for understanding how microbial co-infections may influence oral cancer, the evidence remains preliminary and largely associative. To support these mechanistic hypotheses, future studies should give top priority to in vivo models, bigger patient cohorts, and longitudinal clinical studies.
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Affiliation(s)
- Rancés Blanco
- Independent Researcher, Av. Vicuña Mackenna Poniente 6315, La Florida 8240000, Chile
| | - Juan P. Muñoz
- Laboratorio de Bioquímica, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile
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10
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Quisias J, Gill MJ, Coburn SB, Krentz HB, Beckthold B, Fonseca K, Parkins MD, Lang R. Cytomegalovirus serostatus among people with HIV, characterizing the prevalence, risk factors, and association with immune recovery. HIV Med 2025. [PMID: 40295208 DOI: 10.1111/hiv.70036] [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: 02/14/2025] [Accepted: 04/14/2025] [Indexed: 04/30/2025]
Abstract
INTRODUCTION Cytomegalovirus (CMV) infection is common among people with HIV (PWH), and may be associated with negative outcomes. We aimed to identify the seroprevalence of CMV between 01 January 1998 and 01 June 2022 among PWH accessing care at the Southern Alberta Clinic (SAC) and the associated risk factors. We also aimed to assess the impact of CMV seropositivity on CD4+ T-cells and CD4+/CD8+ ratio recovery among PWH who maintain HIV viral suppression. METHODS Poisson regression models with robust variance estimated crude and adjusted prevalence ratios and 95% confidence intervals to identify risk factors for CMV seronegativity. Among PWH maintaining viral suppression, trends in the median CD4+ T-cell count and CD4+/CD8+ ratio were visualized, and continuous time-to-event Cox proportional hazard models estimated hazards ratios (aHR) for CD4+ cell count recovery to ≥500 cells/mm3 and CD4+/CD8+ ratio of >1 at 10 years by CMV serostatus. RESULTS Among 3249 PWH, 2954 (91%) were CMV seropositive. CMV seronegativity was associated with younger ages, male sex, non-Hispanic white race and an education of ≥12 years. While CMV seronegativity did not affect CD4+ T-cell recovery following HIV viral suppression (aHR 1.15 [0.89-1.48]), it was associated with a greater likelihood of CD4+/CD8+ ratio normalization (aHR 2.38 [1.85-3.07]) at 10 years of follow-up. CONCLUSIONS CMV is a common coinfection among PWH. We found that CMV positivity among PWH maintaining HIV viral suppression, while not associated with CD4+ T-cell recovery, was associated with a reduced CD4+/CD8+ ratio recovery. This suggests an association with chronic CMV infection-mediated immune activation and inflammation among PWH.
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Affiliation(s)
- Joshua Quisias
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - M John Gill
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Southern Alberta Clinic, Alberta Health Services, Calgary, Alberta, Canada
- Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Sally B Coburn
- Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Hartmut B Krentz
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Southern Alberta Clinic, Alberta Health Services, Calgary, Alberta, Canada
| | - Brenda Beckthold
- Southern Alberta Clinic, Alberta Health Services, Calgary, Alberta, Canada
| | - Kevin Fonseca
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
- Alberta Public Health Laboratory, Alberta Health Services, Calgary, Alberta, Canada
| | - Michael D Parkins
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Raynell Lang
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Southern Alberta Clinic, Alberta Health Services, Calgary, Alberta, Canada
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
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11
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Schlaeffer-Yosef T, Nesher L. Tackling CMV in Transplant Recipients: Past, Present, and Future. Infect Dis Ther 2025:10.1007/s40121-025-01159-6. [PMID: 40289195 DOI: 10.1007/s40121-025-01159-6] [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: 03/07/2025] [Accepted: 04/09/2025] [Indexed: 04/30/2025] Open
Abstract
Cytomegalovirus (CMV), a beta-herpesvirus capable of maintaining lifelong latency, presents a substantial risk to transplant recipients, resulting in significant morbidity and mortality among both hematopoietic stem cell and solid organ transplantation recipients. Recent advances have shifted management from reactive approaches, such as preemptive therapy, to preventive strategies to reduce active infections and disease burden. Letermovir, a selective CMV terminase inhibitor, has emerged as a critical prophylactic agent in high-risk transplant populations, significantly lowering infection rates and improving survival with fewer adverse effects than older antivirals. Maribavir, a UL97 kinase inhibitor, is another recently approved promising option for treating CMV, especially in patients with ganciclovir-resistant or refractory CMV infections. Despite these achievements, the risk of late-onset CMV infection after prophylaxis discontinuation remains a significant clinical challenge. Current research seeks to refine prophylactic regimens and develop advanced diagnostic tools, notably interferon-gamma release assays that measure CMV-specific T cell responses. These immunologic assays may help clinicians identify individuals capable of controlling CMV replication, thus guiding the safer discontinuation of prophylaxis and reducing unnecessary drug exposure. Conversely, patients lacking robust immune reconstitution could be targeted for extended prophylaxis or closer follow-up. Looking into the future, ongoing innovations in immune monitoring and antiviral development will likely lead to a more personalized approach to CMV prevention and treatment, optimizing care based on patient-specific risk profiles and immune competence. As this field continues to evolve, integrating novel therapies, improved diagnostics, and immunity-driven protocols holds promise for further reducing CMV-related complications and improving overall outcomes for transplant recipients.
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Affiliation(s)
- Tal Schlaeffer-Yosef
- Infectious Diseases Institute, Soroka University Medical Center, and the Faculty of Health Sciences, Ben-Gurion University of the Negev, 1 Rager Street, 84101, Beer-Sheva, Israel
| | - Lior Nesher
- Infectious Diseases Institute, Soroka University Medical Center, and the Faculty of Health Sciences, Ben-Gurion University of the Negev, 1 Rager Street, 84101, Beer-Sheva, Israel.
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Liao J, Wei JH, Liu J, Ren L, Zang N, Liu E. Respiratory virome in hospitalized children and analysis of its correlation with disease severity. Eur J Clin Microbiol Infect Dis 2025:10.1007/s10096-025-05140-6. [PMID: 40285962 DOI: 10.1007/s10096-025-05140-6] [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: 03/16/2025] [Accepted: 04/18/2025] [Indexed: 04/29/2025]
Abstract
PURPOSE To investigate the composition of respiratory viromes and their association with disease severity among hospitalized pediatric patients. METHODS Clinical data and metagenomic next-generation sequencing (mNGS) results were collected from pediatric patients hospitalized at the Children's Hospital of Chongqing Medical University between January 2022 and September 2023. The analyzed specimens included sputum and bronchoalveolar lavage fluid (BALF). RESULTS The study included 229 patients (65.07% male, median age 3 years) with 25 sputum and 204 BALF samples, of whom 40.17% met the WHO criteria for severe acute respiratory infection (SARI). Herpesviruses were detected in 166 cases (72.49%), including 85 cases of cytomegalovirus (CMV), 64 cases of Epstein-Barr virus (EBV), 34 cases of human herpesvirus-7 (HHV-7), 12 cases of human herpesvirus-6 (HHV-6), and 6 cases of herpes simplex virus type 1 (HSV-1). Additionally, 53 cases of torque teno virus (TTV) and 7 cases of torque teno mini virus (TLMV) were detected. CMV prevalence was highest in neonates, while EBV peaked in the 3-6 year group (37.78%). HSV-1 and HHV-6 were predominantly identified in severe infections. CONCLUSION Herpesviruses, particularly CMV and EBV, were the most frequently detected viruses, followed by anelloviruses. The age-specific viral distribution patterns provide novel epidemiological perspectives for understanding pediatric respiratory pathogenesis, though their clinical significance requires validation through mechanistic studies. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Jing Liao
- Department of Respiratory Medicine of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, 136 Zhongshan Second Road, Yuzhong District, Chongqing, 400014, China
- Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Jian Hua Wei
- Department of Respiratory Medicine of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, 136 Zhongshan Second Road, Yuzhong District, Chongqing, 400014, China
- Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Jiao Liu
- Department of Respiratory Medicine of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, 136 Zhongshan Second Road, Yuzhong District, Chongqing, 400014, China
- Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Luo Ren
- Department of Respiratory Medicine of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, 136 Zhongshan Second Road, Yuzhong District, Chongqing, 400014, China
- Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Na Zang
- Department of Respiratory Medicine of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, 136 Zhongshan Second Road, Yuzhong District, Chongqing, 400014, China.
- Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China.
| | - Enmei Liu
- Department of Respiratory Medicine of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, 136 Zhongshan Second Road, Yuzhong District, Chongqing, 400014, China.
- Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China.
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13
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Wiemers P, Graf I, Addo MM, Arck PC, Diemert A. Mothers and mosquitoes: climate change contributes to the spread of vector-borne pathogens posing a substantial threat to pregnant women. Semin Immunopathol 2025; 47:25. [PMID: 40272573 PMCID: PMC12021716 DOI: 10.1007/s00281-025-01050-z] [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: 08/07/2024] [Accepted: 03/23/2025] [Indexed: 04/25/2025]
Abstract
Infectious diseases have threatened individuals and societies since the dawn of humanity. Certain population groups, including pregnant women, young children and the elderly, are particularly vulnerable to severe infections. Over the past few centuries, advances in medical standards and the availability of vaccines have reduced infection-related mortality and morbidity rates in industrialized countries. However, the global rise in temperatures and increased precipitation present a new challenge, facilitating the broader distribution of disease vectors, such as mosquitoes, bugs and ticks, to higher altitudes and latitudes. Consequently, epidemic and pandemic outbreaks associated with these vectors, such as Zika, West Nile, dengue, yellow fever, chikungunya and malaria, are increasingly impacting diverse populations. This review comprehensively examines how infections associated with climate change disproportionately affect the health and well-being of pregnant women and their unborn children. There has been a noticeable emergence of vector-borne diseases in Europe. Consequently, we stress the importance of implementing measures that effectively protect pregnant women from these increasing infections globally and regionally. We advocate for initiatives to safeguard pregnant women from these emerging threats, beginning with enhanced education to raise awareness about the evolving risks this particularly vulnerable population faces.
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Affiliation(s)
- Pauline Wiemers
- Division of Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Isabel Graf
- Division of Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marylyn M Addo
- Institute for Infection Research and Vaccine Development, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Department for Clinical Immunology of Infectious Diseases, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- German Center for Infection Research, Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Petra C Arck
- Division of Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- German Center for Child and Adolescent Health, Partner Site Hamburg, Hamburg, Germany.
| | - Anke Diemert
- Division of Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- German Center for Child and Adolescent Health, Partner Site Hamburg, Hamburg, Germany.
- Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251, Hamburg, Germany.
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14
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Peterson C, Miller J, Ryckman BJ, Ganusov VV. Apparent cooperativity between human CMV virions introduces errors in conventional methods of calculating multiplicity of infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.23.650360. [PMID: 40313926 PMCID: PMC12045349 DOI: 10.1101/2025.04.23.650360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
Whether infection of cells by individual virions occurs randomly or if there is some form(s) of competition or cooperativity between individual virions remains largely unknown for most virus-cell associations. Here we studied cooperativity/competition for three different strains of human cytomegalovirus ( HCMV ) on two different cell types (fibroblasts and epithelial cells). By titrating viral inocula concentrations in small steps over several orders of magnitude, and by using flow cytometry to precisely measure frequency of infected cells, we found that for most virus-cell associations, the frequency of cell infection increases faster than linear with an increasing inoculum concentration, indicating cooperativity between individual infecting virions. Mathematical modeling suggests that this apparent cooperativity cannot be explained by heterogeneity in either the infectivity of the individual virions or the resistance of individual cells to infection, or by simple aggregation/clumping of viral particles. Stochastic simulations of two additional alternative models that allow for i) reduction in cell resistance to infection when exposed to multiple virions, or ii) compensation in infectivity of poorly infectious virions when coinfecting cells with more infectious virions, resulted in apparent viral cooperativity. Analysis of other published datasets suggests presence of apparent viral cooperativity for HIV and vaccinia virus, infecting CRFK or HeLa cells, respectively, but not for tobacco mosaic virus forming plaques on plant leaves. We thus 1) propose a methodology to rigorously evaluate apparent cooperativity of viruses infecting target cells, and 2) demonstrate that knowing the degree of virus cooperativity for any given virus-cell combination is important for an accurate quantification of multiplicity of infection ( MOI ). Graphical abstract Infections per cell (IU/cell) and specific infectivity (Genomes/IU) of human cytomegalovirus depend on the infecting dose.
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15
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Chen L, Shang Y, Tian X, Huang Y, Sun Y, Fu C, Bai J, Liu Y. The struggles of breastfeeding mothers of preterm infants: a qualitative study. BMC Pregnancy Childbirth 2025; 25:472. [PMID: 40269858 PMCID: PMC12020087 DOI: 10.1186/s12884-025-07597-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 04/11/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Breast milk, with its rich bioactive components and numerous maternal and infant health benefits, is globally recommended as the ideal food for babies, especially premature infants. With the elevated incidence of premature births, suboptimal breastfeeding rates are detrimental, especially considering numerous efforts to promote breastfeeding. The reasons for breastfeeding cessation remain unclear. This study utilizes the social-ecological system theory to explore reasons for the cessation of breastfeeding among mothers of premature infants in China. METHODS An interpretive phenomenological research design was implemented in Wuhan. Through purposive sampling, 14 mothers of premature infants who had discontinued breastfeeding were recruited in Wuhan, China. Semi-structured interviews were conducted to collect data guided by an interview outline developed by the theoretical framework. Content analysis was applied to analyze the interview data. RESULTS The overarching theme of this study was: "On the journey of breastfeeding, who will hold up the sky for me?" This theme encapsulated the multifaceted challenges faced by mothers before discontinuing breastfeeding and their urgent need for comprehensive support. For these mothers, breastfeeding represented not only a physiological challenge but also a significant psychological and emotional burden. The analysis identified three primary categories: Microsystems-the challenges of breastfeeding and adaptation barriers; Mesosystems-dysfunctional support systems within families and hospitals; and Macrosystems-insufficient social support systems. CONCLUSIONS Mothers of premature infants experienced weakened breastfeeding support systems, highlighting the need for (1) Enhancing psychological support and targeted breastfeeding guidance for mothers of preterm infants; (2) Establishing an evidence-based, coordinated support system that integrates hospital and family networks; (3) Strengthening monitoring and enforcement mechanisms for birth policies, enhancing breastfeeding facilities in public spaces, and improving the capacity for breastfeeding education and promotion within communities.
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Affiliation(s)
- Ling Chen
- Center for Women's and Children's Health Research, Wuhan University School of Nursing, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
- Department of neonatology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yanyan Shang
- Department of neonatology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xuqi Tian
- Center for Women's and Children's Health Research, Wuhan University School of Nursing, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Yingjuan Huang
- Center for Women's and Children's Health Research, Wuhan University School of Nursing, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Yu Sun
- Center for Women's and Children's Health Research, Wuhan University School of Nursing, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Chunhua Fu
- Department of neonatology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jinbing Bai
- Nell Hodgson Woodruff School of Nursing,Emory University , 1520 Clifton Road, Atlanta, GA, 30322, USA
| | - Yanqun Liu
- Center for Women's and Children's Health Research, Research Center for Lifespan Health, Wuhan University School of Nursing, Wuhan University, 115 Donghu Road, Wuhan, 430071, China.
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16
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Milotay G, Little M, Watson RA, Muldoon D, MacKay S, Kurioka A, Tong O, Taylor CA, Nassiri I, Webb LM, Akin-Adigun O, Bremke J, Ye W, Sun B, Sharma PK, Cooper R, Danielli S, Santo FM, Verge de Los Aires A, Niu G, Cohen L, Ng E, Gilchrist JJ, Chong AY, Mentzer A, Woodcock V, Coupe N, Payne MJ, Youdell M, Middleton MR, Klenerman P, Fairfax BP. CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint blockade. Nat Med 2025:10.1038/s41591-025-03647-1. [PMID: 40269332 DOI: 10.1038/s41591-025-03647-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 03/07/2025] [Indexed: 04/25/2025]
Abstract
Cytomegalovirus (CMV) is a globally endemic latent herpes virus that profoundly impacts T cell immunity. We investigated the oncological consequences of CMV infection across 341 prospectively recruited patients receiving immune checkpoint blockade (ICB) for melanoma. CMV+ patients with metastatic melanoma (MM) have higher lymphocyte counts, reduced neutrophil to lymphocyte ratio and divergent CD8+ T cell gene expression. Combination anti-CTLA-4/anti-PD-1 ICB, but not single-agent anti-PD-1 ICB, induces cytotoxicity and CMV-associated gene expression in CD8+ T cells from CMV- patients. Correspondingly, overall survival was independent of CMV serostatus in combination anti-CTLA-4/anti-PD-1 ICB recipients (CMV+ hazard ratio for death: 1.02, P = 0.92), whereas CMV+ single-agent anti-PD-1 ICB recipients had improved overall survival (CMV+ hazard ratio for death: 0.37, P < 0.01), a finding also seen in CMV+ adjuvant single-agent anti-PD-1 ICB recipients (CMV+ hazard ratio for recurrence: 0.19, P = 0.03). We identify TBX21, encoding T-bet, as a transcriptional driver of CMV-associated CD8+ T cell gene expression, finding that TBX21 expression is predictive of overall survival (hazard ratio: 0.62, P = 0.026). CMV+ patients unexpectedly show reduced cumulative incidence of grade 3+ immune-related adverse events at 6 months (0.30 versus 0.52, P = 2.2 × 10-5), with lower incidence of colitis (P = 7.8 × 10-4) and pneumonitis (P = 0.028), an effect replicated in non-melanoma ICB recipients (n = 58, P = 0.044). Finally, we find reduced CMV seropositivity rates in patients with MM compared with UK Biobank controls (odds ratio: 0.52, P = 1.8 × 10-4), indicating CMV seropositivity may protect against MM. Specifically, patients with BRAF-mutated MM are less likely to be CMV+ (odds ratio = 2.2, P = 0.0054), while CMV- patients present 9 yr earlier with BRAF wild-type MM (P = 1.3 × 10-4). This work reveals an interaction between CMV infection, MM development according to BRAF status and response to ICB, while demonstrating CMV infection is protective against severe ICB immune-related adverse events, highlighting the potential importance of previous infection history and chronic immune activation in MM development and immunotherapy outcomes.
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Affiliation(s)
- Gusztav Milotay
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Martin Little
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
- Oxford Cancer-CRUK Oxford Centre, University of Oxford, Churchill Hospital, Oxford, UK
- Kennedy Institute for Rheumatology, University of Oxford, Oxford, UK
| | - Robert A Watson
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
- Oxford Cancer-CRUK Oxford Centre, University of Oxford, Churchill Hospital, Oxford, UK
- Kennedy Institute for Rheumatology, University of Oxford, Oxford, UK
| | - Dylan Muldoon
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Sophie MacKay
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Ayako Kurioka
- The Centre for Human Genetics, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
| | - Orion Tong
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Chelsea A Taylor
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Isar Nassiri
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Louisa M Webb
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Oluwafemi Akin-Adigun
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Julia Bremke
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Weiyu Ye
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Bo Sun
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK
| | - Piyush Kumar Sharma
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Ros Cooper
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Sara Danielli
- Oxford Cancer-CRUK Oxford Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Flavia Matos Santo
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Alba Verge de Los Aires
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Guangyi Niu
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Lea Cohen
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Esther Ng
- Kennedy Institute for Rheumatology, University of Oxford, Oxford, UK
| | - James J Gilchrist
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Paediatrics, University of Oxford, Oxford, UK
| | - Amanda Y Chong
- The Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Alex Mentzer
- The Centre for Human Genetics, University of Oxford, Oxford, UK
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
| | - Victoria Woodcock
- Department of Oncology, University of Oxford, Oxford, UK
- Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Nicholas Coupe
- Department of Oncology, University of Oxford, Oxford, UK
- Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Miranda J Payne
- Department of Oncology, University of Oxford, Oxford, UK
- Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Michael Youdell
- Oxford Cancer-CRUK Oxford Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Mark R Middleton
- Department of Oncology, University of Oxford, Oxford, UK
- Oxford Cancer-CRUK Oxford Centre, University of Oxford, Churchill Hospital, Oxford, UK
- Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Paul Klenerman
- The Centre for Human Genetics, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
| | - Benjamin P Fairfax
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
- Department of Oncology, University of Oxford, Oxford, UK.
- Oxford Cancer-CRUK Oxford Centre, University of Oxford, Churchill Hospital, Oxford, UK.
- Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
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Rimal Y, Sharma N, Paudel S, Alsadoon A, Koirala MP, Gill S. Comparative analysis of heart disease prediction using logistic regression, SVM, KNN, and random forest with cross-validation for improved accuracy. Sci Rep 2025; 15:13444. [PMID: 40251253 PMCID: PMC12008431 DOI: 10.1038/s41598-025-93675-1] [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: 04/21/2024] [Accepted: 03/10/2025] [Indexed: 04/20/2025] Open
Abstract
This primary research paper emphasizes cross-validation, where data samples are reshuffled in each iteration to form randomized subsets divided into n folds. This method improves model performance and achieves higher accuracy than the baseline model. The novelty lies in the data preparation process, where numerical features were imputed using the mean, categorical features were imputed using chi-square methods, and normalization was applied. This research study involves transforming the original datasets and comparative model analysis of four Logistic Regression (LR), Support Vector Machine (SVM), K-Nearest Neighbor (KNN), and Random Forest (RF) cross-validation methodologies to heart disease open datasets. The objective is to easily identify the average accuracy of model predictions and subsequently make recommendations for model selection based on data preprocessing cross-validation model increased (5 to 14%) more than baseline model for best model selection. From comparing each model's accuracy scores, it is found that the logistic regression and k-nearest neighbor models achieved the highest accuracy of 81% among the four models when single accuracy is a concern. However, the random forest model summary statistics attained an F1 score of 95%, precision (96%), and recall (97%), indicating the highest overall macro accuracy score. These findings can be further compared using learning curve validation. Conversely, the logistic regression model exhibited the lowest accuracy of 84% among the four machine learning models. However, this research does not cover hyperparameter optimization, which could potentially improve model performance.
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Affiliation(s)
- Yagyanath Rimal
- IIS (Deemed to be University), Jaipur, India.
- Pokhara University, Pokhara, Nepal.
| | | | | | - Abeer Alsadoon
- Western Sydney University (WSU), Sydney, Australia
- Asia Pacific International College (APIC), Sydney, Australia
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18
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Kang H, Wang L, Chen Y, Dong T, Pan Y, Liu Q. Screening and prenatal diagnosis of fetal cytomegalovirus infection: experience in a western Chinese city. BMC Infect Dis 2025; 25:542. [PMID: 40240971 PMCID: PMC12004672 DOI: 10.1186/s12879-025-10910-w] [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: 03/03/2025] [Accepted: 04/03/2025] [Indexed: 04/18/2025] Open
Abstract
OBJECTIVE To explore the application value of serology testing and fetal ultrasound examination in screening for fetal cytomegalovirus(CMV) infection. To explore the application value of CMV polymerase chain reaction (PCR) in amnio fluids in prenatal diagnosis of fetal CMV infection. METHODS This is a retrospective study performed at Chengdu Women's and Children's Central Hospital between 2021 and 2024. The baseline of preconception CMV infections and recent infections were investigated via serology testing. Pregnant women with suspicious serology for recent infection and/or ultrasound abnormalities suggestive of fetal infection underwent amniocentesis to obtain amniotic fluid for CMV PCR. The pregnancy outcomes of women with suspicious serology for recent infection and those who underwent amniocentesis were analyzed. RESULTS The seroprevalence was 95.65%(55262/57778) and 0.99%(571/57778) for immunoglobulin G(IgG) and immunoglobulin M (IgM) antibodies respectively. Among the 315 pregnant women with positive IgM results who performed CMV IgG avidity index and/or dynamic IgM/ IgG tests, only 2.22%(7/315) confirmed recent infection and 2.54%(8/315) suspected recent infection: three terminated pregnancies including one with positive CMV PCR results and two with other reasons, and 12 gave birth to asymptomatic babies. 576 pregnant women with suspicious serology for recent infection and/or ultrasound abnormalities suggestive of fetal infection performed CMV PCR in amniotic fluid. Among them, we got 438 pregnancy outcomes, including 25 terminated pregnancies, eight stillbirths, and 405 live births. None of the 405 live births had symptoms related to CMV infection at birth, except two with mild hearing loss without known cause. Four fetal infections were diagnosed, including three who performed amniocentesis and CMV PCR and one accidentally diagnosed by copy number variation sequencing(CNV-seq). Three of them were negative for IgM in first-trimester screening. CONCLUSION Ultrasound screening plays a more important role than serology screening in areas with a high seroprevalence of CMV antibodies. Assays for both chromosome disorders and CMV PCR in amniotic fluids should be suggested to pregnant women with ultrasound abnormalities suggestive of fetal infection.
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Affiliation(s)
- Han Kang
- Prenatal diagnosis department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, 1617 RiYue Road, Chengdu, China
| | - Lingxi Wang
- Prenatal diagnosis department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, 1617 RiYue Road, Chengdu, China
| | - Yifei Chen
- Prenatal diagnosis department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, 1617 RiYue Road, Chengdu, China
| | - Ting Dong
- Prenatal diagnosis department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, 1617 RiYue Road, Chengdu, China
| | - Yuchun Pan
- Prenatal diagnosis department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, 1617 RiYue Road, Chengdu, China
| | - Qingsong Liu
- Prenatal diagnosis department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, 1617 RiYue Road, Chengdu, China.
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19
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Lee SH, Ho YR, Li H, Tu YK, Bowman K, Chou EH, Lee YC, Tsai HR, Tsai TY. Prevalence and clinical manifestations of cytomegalovirus infection in patients with Posner-Schlossman syndrome: A systematic review and meta-analysis. Surv Ophthalmol 2025:S0039-6257(25)00068-2. [PMID: 40220961 DOI: 10.1016/j.survophthal.2025.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 04/01/2025] [Accepted: 04/08/2025] [Indexed: 04/14/2025]
Abstract
Posner-Schlossman syndrome (PSS) is thought to be associated with cytomegalovirus (CMV) infection; however, the prevalence of CMV infection and its characteristics in PSS patients varies across studies. Therefore, global estimates of CMV prevalence in PSS are needed to provide clearer insights for informing epidemiological surveillance and guiding treatment strategies. Embase, MEDLINE, Scopus, and Web of Science were searched for population-based, clinic-based, and secondary health care database studies that reported prevalence or incidence of CMV in patient with PSS published between database inception and October 31, 2024. Meta-analysis was conducted by using a random-effects model. The primary outcome was prevalence of CMV infection in patient with PSS. Secondary outcomes were characteristics of CMV infection in patient with PSS, such as corneal endothelial cell density and filtering surgery rate. Twenty-one studies, enrolling 1265 patients with PSS, were included. The pooled prevalence of CMV infection in patients with PSS was 44.5 % (95 % CI: 36.2 %-53.1 %; I2= 73.9 %). The affected eye in patients with CMV infection had significantly lower endothelial density (mean difference, -389.8 cell/mm2; 95 % CI: -553.8 to -225.9 cell/mm2; p < 0.001; I ² = 53.8 %) and a higher risk of requiring filtration surgery than that in patients without CMV infection (pooled OR: 8.9, 95 % CI: 3.0-26.4; p < 0.001; I ² = 0 %). We highlight the prevalence and clinical outcomes of CMV infection in patients with PSS. The causal relationship between CMV infection and PSS requires exploration to inform effective diagnosis and treatment strategies.
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Affiliation(s)
- Ssu-Hsien Lee
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Yan-Rong Ho
- School of Medicine, Tzu Chi University, Hualien, Taiwan; Medical Department, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Hua Li
- Emergency Department, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Yu-Kang Tu
- Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital and School of Dentistry, National Taiwan University, Taipei, Taiwan
| | | | - Eric H Chou
- Department of Emergency Medicine, Baylor Scott & White All Saints Medical Center, Fort Worth, TX, USA
| | - Yuan-Chieh Lee
- Department of Ophthalmology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; Department of Ophthalmology and Visual Science, Tzu Chi University, Hualien, Taiwan
| | - Hou-Ren Tsai
- Department of Ophthalmology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
| | - Tou-Yuan Tsai
- School of Medicine, Tzu Chi University, Hualien, Taiwan; Emergency Department, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
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20
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Świątkowska-Freund M, Bednarek S, Sasak-Cieślar N, Kocięcka N, Powroźnik P, Waldman A. Cytomegalovirus Seroprevalence in Northern Poland in the Population Planning Pregnancy and Pregnant Women. Viruses 2025; 17:537. [PMID: 40284980 PMCID: PMC12031441 DOI: 10.3390/v17040537] [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: 03/06/2025] [Revised: 04/02/2025] [Accepted: 04/03/2025] [Indexed: 04/29/2025] Open
Abstract
Cytomegalovirus is an enveloped DNA virus. All forms of CMV infection-primary infection, reactivation, and infection with a different strain-may be asymptomatic. The risk of vertical transmission in the periconceptional period is approximately 20%, the risk of primary infection in the first trimester is approximately 30%, and in the third trimester the risk increases to 70%. However, the most severe forms of congenital cytomegaly in newborns are related to infections in the periconceptional period. Offering a vaccine to the seronegative patients planning pregnancy may decrease incidents of congenital cytomegaly in neonates. The authors performed retrospective analysis of seroprevalence of CMV in 909 women who reported for pre-conceptional visits or routine pregnancy follow-ups (2003-2023). In the analyzed group, 577 (63.7%) women were seropositive. No influence related to the women's age and place of residence was found. Higher seroprevalence was observed in women with children or those working in contact with many people. In the group of 332 seronegative patients, 21 (0.6%) were diagnosed with primary infection during pregnancy. Vaccinating 36.3% of patients planning pregnancy could significantly decrease the risk of primary infection during pregnancy, vertical transmission of CMV, and symptomatic infection in the neonates.
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Affiliation(s)
- Małgorzata Świątkowska-Freund
- The Academy of Applied Medical and Social Sciences, Lotnicza 2, 82-300 Elbląg, Poland
- The Ludwik Rydygier Provincial Polyclinical Hospital in Torun, Św. Józefa 53-59, 87-100 Toruń, Poland; (S.B.); (N.S.-C.)
| | - Szymon Bednarek
- The Ludwik Rydygier Provincial Polyclinical Hospital in Torun, Św. Józefa 53-59, 87-100 Toruń, Poland; (S.B.); (N.S.-C.)
| | - Natalia Sasak-Cieślar
- The Ludwik Rydygier Provincial Polyclinical Hospital in Torun, Św. Józefa 53-59, 87-100 Toruń, Poland; (S.B.); (N.S.-C.)
| | - Natalia Kocięcka
- Powiatowe Centrum Zdrowia w Kartuzach, Ceynowy 7, 83-300 Kartuzy, Poland;
| | - Paweł Powroźnik
- Medical University of Gdansk, Marii Skłodowskiej-Curie 3a, 80-210 Gdańsk, Poland;
| | - Anna Waldman
- Poznan University of Medical Sciences, Collegium Maius, Fredry 10, 61-701 Poznań, Poland;
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21
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Boquett JA, Sauter J, Schmidt AH, Maiers M, Hollenbach JA. Human leukocyte antigen variation is associated with cytomegalovirus serostatus in healthy individuals. Am J Hum Genet 2025; 112:913-926. [PMID: 40049169 DOI: 10.1016/j.ajhg.2025.02.007] [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: 09/12/2024] [Revised: 02/05/2025] [Accepted: 02/07/2025] [Indexed: 03/12/2025] Open
Abstract
Cytomegalovirus (CMV) is a common β-herpes virus worldwide with an estimated seroprevalence among the general population of 83%. Primary infection is usually benign; however, CMV can cause severe morbidity in newborns in whom it is acquired congenitally, as well as immunocompromised individuals. Understanding the role of immunogenetic variation in risk for CMV infection can provide insight into the immune control of this ubiquitous pathogen. Here, we evaluated the association of human leukocyte antigen (HLA) genetic variation with CMV seropositivity in more than 518,000 individuals from two independent cohorts. We found three HLA class II alleles (HLA-DRB1∗04:03 with risk; HLA-DRB1∗01:03 and HLA-DRB1∗07:01 with protection) to be significantly associated with CMV serostatus across both cohorts and in multiple population subgroups. Interestingly, HLA-DRB1∗04:03 and HLA-DRB1∗01:03, the alleles with the strongest observed effect, are relatively rare, while common homologous alleles show no association with CMV. We show that these differences are mediated by changes in charge and volume to two key pockets in the peptide-binding groove of the HLA molecule, providing a structural basis for the observed association. Our results provide population-scale evidence for the role of HLA in mediating infection with this ubiquitous human virus and a framework for understanding immunological conditions necessary for efficient viral control.
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Affiliation(s)
- Juliano A Boquett
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
| | | | | | - Martin Maiers
- CIBMTR (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, MN, USA
| | - Jill A Hollenbach
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
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22
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Tzialla C, Salomè S, Mondì V. Clinical Manifestations of Non-Congenital CMV Infection in Infants and Immunocompetent Children: Review of Cases from the Past Decade. Microorganisms 2025; 13:772. [PMID: 40284610 PMCID: PMC12029332 DOI: 10.3390/microorganisms13040772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 03/22/2025] [Accepted: 03/25/2025] [Indexed: 04/29/2025] Open
Abstract
Cytomegalovirus (CMV), the largest of the herpes viruses, is a widespread virus that commonly infects people of all ages. CMV can cause a spectrum of clinical manifestations, ranging from asymptomatic infection to severe disease, particularly in immunocompromised hosts. However, postnatal and acquired CMV infections in immunocompetent children remain under-documented in the literature. In this review, we examine studies published over the past decade to explore the clinical manifestations of CMV infections in the pediatric population, focusing on the variety of symptoms and the severity with which the infection can present. Papers published between 1 January 2014 and 2 December 2024 were selected from PubMed/MEDLINE, Embase, Scopus, and Web of Science. The search was conducted using the following keywords: "cytomegalovirus", "child", and "immunocompetent". The target population ranged from 0 to 17 years of age, with congenital and perinatal infections excluded. Despite the clinical significance of CMV in immunocompetent infants and children, there is a lack of consensus on the use and duration of antiviral therapy. This article aims to enhance clinicians' understanding of the various presentations of CMV infection in immunocompetent children, with the goal of facilitating earlier diagnosis and appropriate management. The reviewed papers indicated that postnatal CMV results in liver symptoms in 67% of cases, followed by hematological disorders and gastrointestinal pathology. In older children, primary infection leads to liver disease in 51% of cases, with greater neurological and pulmonary involvement compared to that in infants. By highlighting the wide-ranging clinical effects of CMV, we hope to improve physicians' ability to recognize and subsequently treat this often overlooked condition in pediatric patients.
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Affiliation(s)
- Chryssoula Tzialla
- Neonatal and Pediatric Unit, Polo Ospedaliero Oltrepò, ASST Pavia, 27058 Voghera, Italy
| | - Serena Salomè
- Division of Neonatology, Department of Translational Medical Sciences, University of Naples Federico II, 80138 Naples, Italy;
| | - Vito Mondì
- Neonatology and Neonatal Intensive Care Unit, AO San Giovanni-Addolorata, 00184 Rome, Italy;
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23
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Shulgina SM, Osetsky NY, Rykova MP, Antropova EN, Zhuravleva TV, Shmarov VA, Kutko OV, Vlasova DD, Kotikova AA, Orlova KD, Zhirova EA, Ponomarev SA. Reactivation of latent human intracellular infections during a months-long expedition at the Antarctic Vostok station. Sci Rep 2025; 15:9980. [PMID: 40121316 PMCID: PMC11929851 DOI: 10.1038/s41598-025-94539-4] [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: 07/31/2024] [Accepted: 03/14/2025] [Indexed: 03/25/2025] Open
Abstract
The complex of spaceflight factors has a significant impact on the immunity functional activity. This influence is probably caused by factors such as isolation, monotony, physical inactivity, sensory deprivation, and increased psycho-emotional tension. Long-term wintering at polar stations can be the ground-based model that is most similar to space flight conditions. This research focused on examining the reactivation of latent human pathogens among 11 participants of the 64th Russian Antarctic expedition to Vostok station. Plasma, saliva and urine samples collected before arriving at the station and also during the wintering were studied. Even at the pre-expedition period, DNA of at least one of the studied pathogens was detected in the saliva and plasma of 10 out of 11 (90%) expedition members. During the wintering all the participants showed changes in the Epstein-Barr virus DNA concentration in body fluids. Moreover, 9 out of 11 (80%) participants showed the human herpes virus type 6 shedding in the saliva and/or plasma. Herpes simplex virus types 1 and 2 shedding was observed in 18% of subjects as well. Additionally, there was an assumption made about the relationship between dynamics of latent pathogen shedding, geomagnetic activity, and the psychological state of expedition participants.
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Affiliation(s)
- Sofiya M Shulgina
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation.
| | - Nikolay Y Osetsky
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation
| | - Marina P Rykova
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation
| | - Evgeniya N Antropova
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation
| | - Tatyana V Zhuravleva
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation
| | - Vacheslav A Shmarov
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation
| | - Olga V Kutko
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation
| | - Dariya D Vlasova
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation
| | - Anastasiya A Kotikova
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation
- Pirogov Russian National Research Medical University (Pirogov Medical University), Moscow, 117997, Russian Federation
| | - Kseniya D Orlova
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation
| | - Elina A Zhirova
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation
| | - Sergey A Ponomarev
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russian Federation
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24
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Pamela RH, Minerva MR, Ernesto CMM, Manuel MAJ, Norberto SE, Francisco AH, de la Torre Silvia MD, Angélica RL, Elva JH, Carlos NEJ, Sara O, Juan XC, Ariadnna CC, Paula FA, José AG. Is the vIL-10 Protein from Cytomegalovirus Associated with the Potential Development of Acute Lymphoblastic Leukemia? Viruses 2025; 17:435. [PMID: 40143362 PMCID: PMC11945621 DOI: 10.3390/v17030435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 03/01/2025] [Accepted: 03/14/2025] [Indexed: 03/28/2025] Open
Abstract
Leukemia is a hematologic malignancy; acute lymphoblastic leukemia (ALL) is the most prevalent subtype among children rather than in adults. Orthoherpesviridae family members produce proteins during latent infection phases that may contribute to cancer development. One such protein, viral interleukin-10 (vIL-10), closely resembles human interleukin-10 (IL-10) in structure. Research has explored the involvement of human cytomegalovirus (hCMV) in the pathogenesis of ALL. However, the limited characterization of its latent-phase proteins restricts a full understanding of the relationship between hCMV infection and leukemia progression. Studies have shown that hCMV induces an inflammatory response during infection, marked by the release of cytokines and chemokines. Inflammation may, therefore, play a role in how hCMV contributes to oncogenesis in pediatric ALL, possibly mediated by latent viral proteins. The classification of a virus as oncogenic is based on its alignment with cancer's established hallmarks. Viruses can manipulate host cellular mechanisms, causing dysregulated cell proliferation, evasion of apoptosis, and genomic instability. These processes lead to mutations, chromosomal abnormalities, and chronic inflammation, all of which are vital for carcinogenesis. This study aims to investigate the role of vIL-10 during the latent phase of hCMV as a potential factor in leukemia development.
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Affiliation(s)
- Ruvalcaba-Hernández Pamela
- Laboratorio de Virología, Unidad de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (R.-H.P.); (M.-D.d.l.T.S.)
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Mata-Rocha Minerva
- Unidad de Investigación en Genética Humana, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Avenida Cuauhtémoc 330, Doctores, Ciudad de México 06720, Mexico; (M.-R.M.); (S.-E.N.)
| | | | - Mejía-Aranguré Juan Manuel
- Laboratorio de Genómica Funcional del Cáncer, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico;
- Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Sánchez-Escobar Norberto
- Unidad de Investigación en Genética Humana, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Avenida Cuauhtémoc 330, Doctores, Ciudad de México 06720, Mexico; (M.-R.M.); (S.-E.N.)
- Facultad de Medicina y Cirugía, Universidad Autónoma “Benito Juárez” de Oaxaca, Oaxaca City 68120, Mexico
| | - Arenas-Huertero Francisco
- Laboratorio de Investigación en Patología Experimental, Hospital Infantil de México Federico Gómez, Ciudad de México 06720, Mexico;
| | - Melchor-Doncel de la Torre Silvia
- Laboratorio de Virología, Unidad de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (R.-H.P.); (M.-D.d.l.T.S.)
| | - Rangel-López Angélica
- Laboratorio de Virología, Unidad de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (R.-H.P.); (M.-D.d.l.T.S.)
| | - Jiménez-Hernández Elva
- Departamento de Oncología, Hospital Pediátrico Moctezuma SEDESA, Universidad Autónoma Metropolitana, Mexico City 09769, Mexico;
| | - Nuñez-Enriquez Juan Carlos
- Unidad de Investigación Médica en Epidemiología Clínica, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico;
| | - Ochoa Sara
- Laboratorio de Bacteriología Intestinal, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (O.S.); (X.-C.J.)
| | - Xicohtencatl-Cortes Juan
- Laboratorio de Bacteriología Intestinal, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (O.S.); (X.-C.J.)
| | - Cruz-Córdova Ariadnna
- Laboratorio de Inmunoquímica, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico;
| | | | - Arellano-Galindo José
- Laboratorio de Virología, Unidad de Investigación en Enfermedades Infecciosas, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; (R.-H.P.); (M.-D.d.l.T.S.)
- Centro Interdisciplinario de Ciencias de la Salud Unidad Milpa Alta Instituto Politécnico Nacional, Mexico City 12000, Mexico
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25
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Lin MH, Hu LJ, Miller JS, Huang XJ, Zhao XY. CAR-NK cell therapy: a potential antiviral platform. Sci Bull (Beijing) 2025; 70:765-777. [PMID: 39837721 DOI: 10.1016/j.scib.2025.01.002] [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: 09/09/2024] [Revised: 10/31/2024] [Accepted: 12/11/2024] [Indexed: 01/23/2025]
Abstract
Viral infections persist as a significant cause of morbidity and mortality worldwide. Conventional therapeutic approaches often fall short in fully eliminating viral infections, primarily due to the emergence of drug resistance. Natural killer (NK) cells, one of the important members of the innate immune system, possess potent immunosurveillance and cytotoxic functions, thereby playing a crucial role in the host's defense against viral infections. Chimeric antigen receptor (CAR)-NK cell therapy has been developed to redirect the cytotoxic function of NK cells specifically towards virus-infected cells, further enhancing their cytotoxic efficacy. In this manuscript, we review the role of NK cells in antiviral infections and explore the mechanisms by which viruses evade immune detection. Subsequently, we focus on the optimization strategies for CAR-NK cell therapy to address existing limitations. Furthermore, we discuss significant advancements in CAR-NK cell therapy targeting viral infections, including those caused by severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus, hepatitis B virus, human cytomegalovirus, and Epstein-Barr virus.
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Affiliation(s)
- Ming-Hao Lin
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Cell and Gene Therapy for Hematologic Malignancies, Peking University, Beijing 100044, China
| | - Li-Juan Hu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Cell and Gene Therapy for Hematologic Malignancies, Peking University, Beijing 100044, China
| | - Jeffrey S Miller
- Department of Medicine, University of Minnesota, Minneapolis, 55455, USA.
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Cell and Gene Therapy for Hematologic Malignancies, Peking University, Beijing 100044, China; Peking-Tsinghua Center for Life Sciences, Beijing 100871, China.
| | - Xiang-Yu Zhao
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Cell and Gene Therapy for Hematologic Malignancies, Peking University, Beijing 100044, China.
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26
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Dickmander RJ, Lenarcic EM, Sears JD, Hale AE, Moorman NJ. RNA-targeted proteomics identifies YBX1 as critical for efficient HCMV mRNA translation. Proc Natl Acad Sci U S A 2025; 122:e2421155122. [PMID: 40035757 PMCID: PMC11912382 DOI: 10.1073/pnas.2421155122] [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: 10/15/2024] [Accepted: 01/17/2025] [Indexed: 03/06/2025] Open
Abstract
Viruses have evolved unique strategies to circumvent host control of protein synthesis and enable viral protein synthesis in the face of the host response. Defining the factors that regulate viral messenger RNA (mRNA) translation is thus critical to understand how viruses replicate and cause disease. To identify factors that might regulate viral mRNA translation, we developed a technique for identifying proteins associated with a native RNA expressed from its endogenous promoter and genomic locus. This approach uses a guide RNA to target dCas13b fused to a biotin ligase domain to a specific RNA, where it covalently labels proteins in close proximity. Using this approach, we identified multiple proteins associated with transcripts encoding the human cytomegalovirus (HCMV) IE1 and IE2 proteins and found that several associated proteins positively or negatively regulate HCMV replication. We confirmed that one such protein, the cellular Y-box binding protein 1 (YBX1), binds to HCMV immediate early mRNAs and is required for efficient viral protein expression and virus replication. Ablating YBX1 expression reduced the association of HCMV immediate early mRNAs with polysomes, demonstrating a role for YBX1 as a positive regulator of viral RNA translation. These results provide a powerful tool for unraveling RNA-protein interactions that can be used in a wide range of biological processes and reveal a role for YBX1 as a critical regulator of HCMV immediate early gene expression.
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Affiliation(s)
- Rebekah J. Dickmander
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC27599
| | - Erik M. Lenarcic
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC27599
| | - John D. Sears
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC27599
| | - Andrew E. Hale
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC27599
| | - Nathaniel J. Moorman
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC27599
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27
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Okalany NRA, Engebretsen IMS, Mukunya D, Chebet M, Okello F, Weeks AD, Mwanda E, Muhindo R, Bisso F, Tylleskär T, Olupot-Olupot P, Burgoine K. Congenital cytomegalovirus in eastern Uganda: prevalence and outcomes. BMC Pediatr 2025; 25:179. [PMID: 40065261 PMCID: PMC11895346 DOI: 10.1186/s12887-025-05518-7] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) infection poses risks to both maternal and neonatal health, however there are limited comprehensive data on congenital CMV in low-resource settings where the virus is widespread, particularly among women of reproductive age. Our research in eastern Uganda aimed to assess the prevalence of congenital CMV and outcomes among infants to inform public health policies and interventions in similar settings, addressing a significant gap in current knowledge. METHODS We conducted a descriptive study, nested within the BabyGel Trial, across Mbale and Budaka districts in eastern Uganda, between May 2023 and January 2024. Infants underwent saliva sampling within the first week of life, which was validated through urine polymerase chain reaction testing within the first 21 days of life. At three months of age, a cranial ultrasound examination, neurological examination, developmental evaluation, and audiological assessment were conducted for all infants diagnosed with congenital CMV infection. Statistical analyses were performed using Stata 17.0. RESULTS Congenital CMV infection was found in 5 out of 1,265 newborns tested, indicating a prevalence of 0.4% (95% CI: 0.16 to 0.96). Of these 5 infected infants, two experienced febrile illness at birth and required hospitalisation within the first week of life, and three had findings on ultrasound examination consistent with congenital cytomegalovirus during the neonatal period. Audiologic follow-up until three months of age revealed that three infants had failed unilateral and bilateral hearing screening. Neurodevelopment assessments using the Malawi Development Assessment Tool fell within optimal ranges for all 5 infants; however, when evaluated using the Hammersmith Infant Neurological Examination, four infants scored below optimal levels. CONCLUSION Our community-based study revealed a low prevalence of congenital CMV infection. Further longitudinal multi-site research is needed to assess the generalisability of these findings. Also, long-term follow-up of children is crucial to understanding the outcomes and sequelae of infected infants to inform prevention strategies, targeted interventions and scalable screening frameworks in resource-limited settings.
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Affiliation(s)
- Noela Regina Akwi Okalany
- Centre for International Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
| | - Ingunn Marie S Engebretsen
- Centre for International Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
| | - David Mukunya
- Department of Community and Public Health, Busitema University, Mbale, Uganda
- Department of Research, Nikao Medical Center, Kampala, Uganda
| | - Martin Chebet
- Centre for International Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
- Department of Paediatrics and Child Health, Faculty of Health Sciences, Busitema University, Mbale, Uganda
| | - Francis Okello
- Centre for International Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
- Department of Community and Public Health, Busitema University, Mbale, Uganda
| | - Andrew D Weeks
- Sanyu Research Unit, Department of Women's and Children's Health, University of Liverpool, Crown Street, Liverpool, L8 7SS, UK
| | - Edrin Mwanda
- Mbale Clinical Research Institute, Mbale, Uganda
| | - Rita Muhindo
- Mbale Clinical Research Institute, Mbale, Uganda
| | - Fred Bisso
- Mbale Regional Referral Hospital, Mbale, Uganda
| | - Thorkild Tylleskär
- Centre for International Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
| | - Peter Olupot-Olupot
- Department of Community and Public Health, Busitema University, Mbale, Uganda
- Mbale Clinical Research Institute, Mbale, Uganda
| | - Kathy Burgoine
- Centre for International Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
- Mbale Clinical Research Institute, Mbale, Uganda
- Mbale Regional Referral Hospital, Mbale, Uganda
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Borrego-Ruiz A, Borrego JJ. Involvement of virus infections and antiviral agents in schizophrenia. Psychol Med 2025; 55:e73. [PMID: 40059820 PMCID: PMC12055031 DOI: 10.1017/s0033291725000467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 02/06/2025] [Accepted: 02/12/2025] [Indexed: 05/08/2025]
Abstract
BACKGROUND Schizophrenia is a chronic and complex mental disorder resulting from interactions between cumulative and synergistic genetic and environmental factors. Viral infection during the prenatal stage constitutes one of the most relevant risk factors for the development of schizophrenia later in adulthood. METHODS A narrative review was conducted to explore the link between viral infections and schizophrenia, as well as the neuropsychiatric effects of antiviral drugs, particularly in the context of this specific mental condition. Literature searches were performed using the PubMed, Scopus, and Web of Science databases. RESULTS Several viral infections, such as herpesviruses, influenza virus, Borna disease virus, and coronaviruses, can directly or indirectly disrupt normal fetal brain development by modifying gene expression in the maternal immune system, thereby contributing to the pathophysiological symptoms of schizophrenia. In addition, neuropsychiatric effects caused by antiviral drugs are frequent and represent significant adverse outcomes for viral treatment. CONCLUSIONS Epidemiological evidence suggests a potential relationship between viruses and schizophrenia. Increases in inflammatory cytokine levels and changes in the expression of key genes observed in several viral infections may constitute potential links between these viral infections and schizophrenia. Furthermore, antivirals may affect the central nervous system, although for most drugs, their mechanisms of action are still unclear, and a strong relationship between antivirals and schizophrenia has not yet been established.
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Affiliation(s)
- Alejandro Borrego-Ruiz
- Departamento de Psicología Social y de las Organizaciones, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Juan J. Borrego
- Departamento de Microbiología, Universidad de Málaga, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA, Plataforma BIONAND, Málaga, Spain
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Stark A, Crooks CM, Permar SR, Weimer KED. Neonatal Cytomegalovirus Infection: Advocacy, Legislation, and Changing Practice. Clin Perinatol 2025; 52:115-132. [PMID: 39892947 DOI: 10.1016/j.clp.2024.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Cytomegalovirus (CMV) is the most common intrauterine infection. While only 10% to 15% of infants display symptoms at birth, 25% of infants with congenital CMV (cCMV) will develop sequelae such as sensorineural hearing loss and neurodevelopmental impairment by the age of 2 years. Although antiviral therapy and early intervention services can improve outcomes for infected infants, cCMV has a substantial economic impact. Studies show that both targeted and universal screenings are cost-effective, but targeted screening misses many infected infants at risk for sequelae. The state-based approach to cCMV screening in the United States varies from universal, targeted, education only to no requirements.
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Affiliation(s)
- Ashley Stark
- Department of Pediatrics, Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710, USA
| | - Chelsea M Crooks
- Department of Pediatrics, Weill Cornell Medicine, 413 East 69th Street, BB-622, Belfer Research Building, New York, NY 10021, USA
| | - Sallie R Permar
- Department of Pediatrics, Weill Cornell Medicine, 525 East 68th Street, M-622, Box 225, New York, NY 10065, USA
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van den Dijssel J, Konijn VAL, Duurland MC, de Jongh R, Koets L, Veldhuisen B, Raaphorst H, Turksma AW, Freen‐van Heeren JJ, Steenhuis M, Rispens T, van der Schoot CE, van Ham SM, van Lier RAW, van Gisbergen KPJM, ten Brinke A, van de Sandt CE. Age and Latent Cytomegalovirus Infection Do Not Affect the Magnitude of De Novo SARS-CoV-2-Specific CD8 + T Cell Responses. Eur J Immunol 2025; 55:e202451565. [PMID: 40071711 PMCID: PMC11898545 DOI: 10.1002/eji.202451565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 01/16/2025] [Accepted: 01/17/2025] [Indexed: 03/15/2025]
Abstract
Immunosenescence, age-related immune dysregulation, reduces immunity upon vaccinations and infections. Cytomegalovirus (CMV) infection results in declining naïve (Tnaïve) and increasing terminally differentiated (Temra) T cell populations, further aggravating immune aging. Both immunosenescence and CMV have been speculated to hamper the formation of protective T-cell immunity against novel or emerging pathogens. The SARS-CoV-2 pandemic presented a unique opportunity to examine the impact of age and/or CMV on the generation of de novo SARS-CoV-2-specific CD8+ T cell responses in 40 younger (22-40 years) and 37 older (50-66 years) convalescent individuals. Heterotetramer combinatorial coding combined with phenotypic markers were used to study 35 SARS-CoV-2 epitope-specific CD8+ T cell populations directly ex vivo. Neither age nor CMV affected SARS-CoV-2-specific CD8+ T cell frequencies, despite reduced total CD8+ Tnaïve cells in older CMV- and CMV+ individuals. Robust SARS-CoV-2-specific central memory CD8+ T (Tcm) responses were detected in younger and older adults regardless of CMV status. Our data demonstrate that immune aging and CMV status did not impact the SARS-CoV-2-specific CD8+ T cell response. However, SARS-CoV-2-specific CD8+ T cells of older CMV- individuals displayed the lowest stem cell memory (Tscm), highest Temra and PD1+ populations, suggesting that age, not CMV, may impact long-term SARS-CoV-2 immunity.
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Affiliation(s)
- Jet van den Dijssel
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Institute for Immunology and Infectious DiseasesAmsterdamThe Netherlands
| | - Veronique A. L. Konijn
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Institute for Immunology and Infectious DiseasesAmsterdamThe Netherlands
| | - Mariël C Duurland
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Institute for Immunology and Infectious DiseasesAmsterdamThe Netherlands
| | - Rivka de Jongh
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Institute for Immunology and Infectious DiseasesAmsterdamThe Netherlands
| | - Lianne Koets
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- National Screening Laboratory of SanquinResearch and Laboratory ServicesAmsterdamThe Netherlands
| | - Barbera Veldhuisen
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Department of Immunohematology DiagnosticsSanquin Diagnostic ServicesAmsterdamThe Netherlands
| | | | | | | | - Maurice Steenhuis
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Theo Rispens
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Institute for Immunology and Infectious DiseasesAmsterdamThe Netherlands
- Amsterdam UMC location Vrije Universiteit AmsterdamMolecular Cell Biology and ImmunologyAmsterdamThe Netherlands
| | - C Ellen van der Schoot
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - S. Marieke van Ham
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Institute for Immunology and Infectious DiseasesAmsterdamThe Netherlands
- Swammerdam Institute for Life SciencesUniversity of AmsterdamAmsterdamThe Netherlands
| | | | - Klaas P. J. M. van Gisbergen
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Institute for Immunology and Infectious DiseasesAmsterdamThe Netherlands
- Physiology and Cancer Programme, Champalimaud ResearchChampalimaud FoundationLisboaPortugal
| | - Anja ten Brinke
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Institute for Immunology and Infectious DiseasesAmsterdamThe Netherlands
| | - Carolien E. van de Sandt
- Sanquin Research and Landsteiner Laboratory, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Institute for Immunology and Infectious DiseasesAmsterdamThe Netherlands
- Department of Microbiology and ImmunologyUniversity of Melbourne at the Peter Doherty Institute for Infection and ImmunityMelbourneVictoriaAustralia
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Reikvam H, Tsykunova G, Sandnes M, Wendelbo Ø. Infectious complications and the utility of serum and cellular markers of infections in the setting of allogeneic hematopoietic stem cell transplantation. Expert Rev Clin Immunol 2025; 21:291-303. [PMID: 39760208 DOI: 10.1080/1744666x.2025.2450014] [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: 02/15/2024] [Revised: 12/24/2024] [Accepted: 01/02/2025] [Indexed: 01/07/2025]
Abstract
INTRODUCTION Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are severely immunocompromised and susceptible to bacterial, viral, and fungal infections. Despite improved anti-microbial prophylaxis and preemptive strategies, bacterial bloodstream infections (BSIs) occur frequently in allo-HSCT recipients and are associated with increased morbidity and mortality. Cytomegalovirus (CMV) and Epstein Barr virus (EBV) are the most relevant viruses following allo-HSCT and remain major concerns. Fungal infections, including those caused by Candida and Aspergillus species, are persistent and feared complications. AREAS COVERED We aim to provide clinicians caring for allo-HSCT recipients with a comprehensive overview of the risk factors that predispose patients to common bacterial, fungal, and viral infections during the first years post-transplant. The focus is on the value of noninvasive diagnostic biomarkers and serological assays in enhancing the early detection and management of these infections. EXPERT OPINION Effective management of infectious complications following allo-HSCT relies on continuous immune recovery monitoring and the implementation of advanced diagnostic methods. Utilizing noninvasive diagnostic methods is crucial for early detection and different intervention strategies. The development and integration of reliable microbiological markers into clinical practice is essential for enhancing patient outcomes and mitigating infection-related risks. Emphasizing diagnostic innovation will be pivotal in advancing patient care post-allo-HSCT.
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Affiliation(s)
- Håkon Reikvam
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
- K.G. Jebsen Center for Myeloid Blood Cancer, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Galina Tsykunova
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Hemato- oncology, Østfold Hospital, Grålum, Norway
| | - Miriam Sandnes
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Øystein Wendelbo
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
- Faculty of Health, VID Specialized University, Bergen, Norway
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Wada Y, Ishioka K, Suzutani T. Determination of whole genome sequence of human cytomegalovirus circulating in Japan and discovery of geographic genome structure in UL148 gene. Virus Res 2025; 353:199540. [PMID: 39894371 PMCID: PMC11846927 DOI: 10.1016/j.virusres.2025.199540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 01/30/2025] [Accepted: 01/31/2025] [Indexed: 02/04/2025]
Abstract
Human cytomegalovirus (HCMV), a member of the Herpesviridae family, is prevalent worldwide. HCMV is generally asymptomatic but causes severe disease in immunocompromised patients or infants who are congenitally infected. Recent advances in sequencing technology have led to the rapid expansion of the HCMV genetic database, providing a comprehensive resource for studying viral genetics. Although genetic investigations have been vigorously performed in European countries, information on the whole-genome sequence of HCMV in the East Asian region remains limited. In this study, we determined whole-genome sequences of two clinical isolates of HCMV circulating in Japan. Partial genome sequences of 26 genes in UL/b' region were also identified using additional seven clinical isolates. Phylogenetic analysis of the UL148 gene revealed a characteristic genetic clade predominantly constructed from HCMV isolates from Japan and China, suggesting a geographic gene structure in the East Asian region. We consider that this research will contribute to expanding the genetic database of HCMV and unveiling novel genetic characteristics of HCMV in Asia.
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Affiliation(s)
- Yuji Wada
- Department of Microbiology, School of Medicine, Fukushima Medical University, Japan.
| | - Ken Ishioka
- Department of Microbiology, School of Medicine, Fukushima Medical University, Japan
| | - Tatsuo Suzutani
- Department of Microbiology, School of Medicine, Fukushima Medical University, Japan
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Nho D, Lee R, Cho SY, Lee DG. How Should Cytomegalovirus Infection Be Managed in Allogeneic Hematopoietic Stem Cell Transplant Recipients? A Clinical Grand Round. Infect Chemother 2025; 57:38-44. [PMID: 40183653 PMCID: PMC11972914 DOI: 10.3947/ic.2024.0140] [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: 12/02/2024] [Accepted: 01/18/2025] [Indexed: 04/05/2025] Open
Abstract
Cytomegalovirus (CMV) is a significant concern for patients with allogeneic hematopoietic cell transplantation (allo-HCT). CMV management differs between institutions due to the lack of local guidelines. Here, we describe a case of refractory/resistant CMV infection treated using our institution's CMV management protocol. A 59-year-old woman who underwent allo-HCT was treated for CMV reactivation. Despite 3 months of valganciclovir administration, serum CMV level surged. CMV gene mutation test revealed a ganciclovir-resistant A594V mutation in the UL97 gene. Treatment was switched to foscarnet until the drug became unavailable nationwide. During the foscarnet shortage, cidofovir was used, leading to a decline in CMV levels when foscarnet was reintroduced and used for 2 months. Following allo-HCT, CMV prophylaxis with letermovir is crucial to prevent reactivation in seropositive recipients. CMV titers should be monitored frequently after allo-HCT. The cutoff value for preemptive therapy varies across institutions, with ganciclovir/valganciclovir usually administered as first-line therapy. Maribavir is an option in cases of ganciclovir/valganciclovir resistance or intolerance. CMV gene mutations should be examined in patients with suspected resistance after 2 weeks of appropriate treatment. This case was discussed at the Clinical Grand Round of the Annual Conference of the Korean Society of Infectious Diseases on November 2, 2023.
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Affiliation(s)
- Dukhee Nho
- Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Catholic Hematology Hospital, Seoul St. Mary's Hospital, Seoul, Korea
| | - Raeseok Lee
- Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Catholic Hematology Hospital, Seoul St. Mary's Hospital, Seoul, Korea
| | - Sung-Yeon Cho
- Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Catholic Hematology Hospital, Seoul St. Mary's Hospital, Seoul, Korea
| | - Dong-Gun Lee
- Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Catholic Hematology Hospital, Seoul St. Mary's Hospital, Seoul, Korea.
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Oliveira ADS, Pereira JG, Nunes GT, Sousa Junior IPD, Sarmento DJDS, Lopes JIF, Amorim Filho L, Paula VSD. Prevalence and investigation of Cytomegalovirus (HCMV) in blood donors from the main blood establishment in Rio de Janeiro/Brazil. Braz J Infect Dis 2025; 29:104508. [PMID: 39922051 PMCID: PMC11848753 DOI: 10.1016/j.bjid.2025.104508] [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: 06/27/2024] [Revised: 12/17/2024] [Accepted: 01/17/2025] [Indexed: 02/10/2025] Open
Abstract
BACKGROUND Human Cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality among pregnant women and immunocompromised patients. HCMV transmission can occur through blood transfusions and typically results in asymptomatic infections in newborns and young individuals or causes symptoms like infectious mononucleosis when symptomatic infections arise. HCMV infection poses a notable risk to transfusion recipients, particularly in vulnerable groups such as premature newborns and immunosuppressed patients. The risk persists even after prophylaxis ends, especially in patients who undergo organ transplantation and receive blood or blood products from a seropositive donor while being seronegative themselves (D+/R-). MATERIALS AND METHODS Here, we investigated the serological and molecular prevalence of HCMV among 980 blood donors from the main blood bank in Rio de Janeiro, Brazil, using chemiluminescence and real-time PCR (TaqMan). The data underwent univariate, bivariate, and multivariate statistical analyses using the SPSS program, version 20.0. RESULTS The average age of donors was 38.53 years, with a majority being male (53.9 %). The prevalence of cytomegalovirus was 88.5 %, and HCMV DNA was detected in 1.2 % of the samples. DISCUSSION Given that there are approximately 100,000 blood donations per year, this prevalence rate is considerably high compared to that in developed countries. These findings underscore the critical need for ongoing surveillance and molecular testing to ensure the safety of blood supplies.
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Affiliation(s)
- Agildo da Silva Oliveira
- Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti/HEMORIO, Rio de Janeiro, RJ, Brazil; Instituto Oswaldo Cruz (Fiocruz), Laboratório de Virologia Molecular e Parasitologia, Rio de Janeiro, RJ, Brazil
| | - Jéssica Gonçalves Pereira
- Instituto Oswaldo Cruz (Fiocruz), Laboratório de Virologia Molecular e Parasitologia, Rio de Janeiro, RJ, Brazil
| | - Gabrielle Tantos Nunes
- Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti/HEMORIO, Rio de Janeiro, RJ, Brazil; Instituto Oswaldo Cruz (Fiocruz), Laboratório de Virologia Molecular e Parasitologia, Rio de Janeiro, RJ, Brazil
| | | | - Dmitry José de Santana Sarmento
- Universidade Estadual da Paraíba, Faculdade de Odontologia, Departamento de Diagnóstico Oral, Araruna, PB, Brazil; Centro Universitário Facisa (UNIFACISA), Departamento de Medicina, Campina Grande, PB Brazil
| | | | - Luiz Amorim Filho
- Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti/HEMORIO, Rio de Janeiro, RJ, Brazil
| | - Vanessa Salete de Paula
- Instituto Oswaldo Cruz (Fiocruz), Laboratório de Virologia Molecular e Parasitologia, Rio de Janeiro, RJ, Brazil.
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Sayadi H, Fromage Y, Labriffe M, Billat PA, Codde C, Arraki Zava S, Marquet P, Woillard JB. Estimation of Ganciclovir Exposure in Adults Transplant Patients by Machine Learning. AAPS J 2025; 27:53. [PMID: 40021573 DOI: 10.1208/s12248-025-01034-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 01/31/2025] [Indexed: 03/03/2025] Open
Abstract
INTRODUCTION Valganciclovir, a prodrug of ganciclovir (GCV), is used to prevent cytomegalovirus infection after transplantation, with doses adjusted based on creatinine clearance (CrCL) to target GCV AUC0-24 h of 40-60 mg*h/L. This sometimes leads to overexposure or underexposure. This study aimed to train, test and validate machine learning (ML) algorithms for accurate GCV AUC0-24 h estimation in solid organ transplantation. METHODS We simulated patients for different dosing regimen (900 mg/24 h, 450 mg/24 h, 450 mg/48 h, 450 mg/72 h) using two literature population pharmacokinetic models, allocating 75% for training and 25% for testing. Simulations from two other literature models and real patients provided validation datasets. Three independent sets of ML algorithms were created for each regimen, incorporating CrCL and 2 or 3 concentrations. We evaluated their performance on testing and validation datasets and compared them with MAP-BE. RESULTS XGBoost using 3 concentrations generated the most accurate predictions. In testing dataset, they exhibited a relative bias of -0.02 to 1.5% and a relative RMSE of 2.6 to 8.5%. In the validation dataset, a relative bias of 1.5 to 5.8% and 8.9 to 16.5%, and a relative RMSE of 8.5 to 9.6% and 10.7% to 19.7% were observed depending on the model used. XGBoost algorithms outperformed or matched MAP-BE, showing enhanced generalization and robustness in their estimates. When applied to real patients' data, algorithms using 2 concentrations showed relative bias of 1.26% and relative RMSE of 12.68%. CONCLUSIONS XGBoost ML models accurately estimated GCV AUC0-24 h from limited samples and CrCL, providing a strategy for optimized therapeutic drug monitoring.
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Affiliation(s)
- Hamza Sayadi
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, Limoges, France
| | - Yeleen Fromage
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, Limoges, France
| | - Marc Labriffe
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, Limoges, France
- Pharmacology & Transplantation, INSERM U1248, Université de Limoges, 2 Rue du Pr Descottes, F-87000, Limoges, France
| | - Pierre-André Billat
- INERIS, Experimental Toxicology and Modeling Unit (TEAM), Parc ALATA BP2, Verneuil en Halatte, France
| | - Cyrielle Codde
- Pharmacology & Transplantation, INSERM U1248, Université de Limoges, 2 Rue du Pr Descottes, F-87000, Limoges, France
- Service de Maladies Infectieuses et Tropicales, CHU Dupuytren, Limoges, France
| | - Selim Arraki Zava
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, Limoges, France
| | - Pierre Marquet
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, Limoges, France
- Pharmacology & Transplantation, INSERM U1248, Université de Limoges, 2 Rue du Pr Descottes, F-87000, Limoges, France
| | - Jean-Baptiste Woillard
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, Limoges, France.
- Pharmacology & Transplantation, INSERM U1248, Université de Limoges, 2 Rue du Pr Descottes, F-87000, Limoges, France.
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Ozer EA, Keskin A, Berrak YH, Cankara F, Can F, Gursoy-Ozdemir Y, Keskin O, Gursoy A, Yapici-Eser H. Shared interactions of six neurotropic viruses with 38 human proteins: a computational and literature-based exploration of viral interactions and hijacking of human proteins in neuropsychiatric disorders. DISCOVER MENTAL HEALTH 2025; 5:18. [PMID: 39987419 PMCID: PMC11846830 DOI: 10.1007/s44192-025-00128-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 01/09/2025] [Indexed: 02/24/2025]
Abstract
INTRODUCTION Viral infections may disrupt the structural and functional integrity of the nervous system, leading to acute conditions such as encephalitis, and neuropsychiatric conditions as mood disorders, schizophrenia, and neurodegenerative diseases. Investigating viral interactions of human proteins may reveal mechanisms underlying these effects and offer insights for therapeutic interventions. This study explores molecular interactions of virus and human proteins that may be related to neuropsychiatric disorders. METHODS Herpes Simplex Virus-1 (HSV-1), Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Influenza A virus (IAV) (H1N1, H5N1), and Human Immunodeficiency Virus (HIV1&2) were selected as key viruses. Protein structures for each virus were accessed from the Protein Data Bank and analyzed using the HMI-Pred web server to detect interface mimicry between viral and human proteins. The PANTHER classification system was used to categorize viral-human protein interactions based on function and cellular localization. RESULTS Energetically favorable viral-human protein interactions were identified for HSV-1 (467), CMV (514), EBV (495), H1N1 (3331), H5N1 (3533), and HIV 1&2 (62425). Besides immune and apoptosis-related pathways, key neurodegenerative pathways, including those associated with Parkinson's and Huntington's diseases, were frequently interacted. A total of 38 human proteins, including calmodulin 2, Ras-related botulinum toxin substrate 1 (Rac1), PDGF-β, and vimentin, were found to interact with all six viruses. CONCLUSION The study indicates a substantial number of energetically favorable interactions between human proteins and selected viral proteins, underscoring the complexity and breadth of viral strategies to hijack host cellular mechanisms. Further in vivo and in vitro validation is required to understand the implications of these interactions.
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Affiliation(s)
| | - Aleyna Keskin
- School of Medicine, Koç University, Istanbul, Turkey
| | | | - Fatma Cankara
- Graduate School of Sciences and Engineering, Computational Sciences and Engineering, Koç University, Istanbul, Turkey
| | - Fusun Can
- Department of Microbiology, School of Medicine, Koç University, Istanbul, Turkey
| | - Yasemin Gursoy-Ozdemir
- Department of Neurology, School of Medicine, Koç University, Istanbul, Turkey
- Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey
| | - Ozlem Keskin
- Department of Chemical and Biological Engineering, College of Engineering, Koç University, Istanbul, Turkey
| | - Attila Gursoy
- Department of Computer Science and Engineering, College of Engineering, Koç University, Istanbul, Turkey.
| | - Hale Yapici-Eser
- Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey.
- Department of Psychiatry, School of Medicine, Koç University, Istanbul, Turkey.
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Hundhausen N, Majumder S, Xiao Y, Haeusl SS, Goehler H, Seal R, Chiarolla CM, Rosenwald A, Eyrich M, Cicin-Sain L, Berberich-Siebelt F. NFAT single-deficient murine T cells reduce the risk of aGvHD while controlling cytomegalovirus infection. iScience 2025; 28:111937. [PMID: 40028277 PMCID: PMC11872454 DOI: 10.1016/j.isci.2025.111937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/13/2024] [Accepted: 01/28/2025] [Indexed: 03/05/2025] Open
Abstract
NFAT is a family of transcription factors whose activation is inhibited by calcineurin inhibitors (CNIs). In allogeneic hematopoietic stem cell transplantation (allo-HCT), CNIs are employed to prevent and treat graft-versus-host disease (GvHD). Unfortunately, control of cytomegalovirus (CMV), which exacerbates clinical outcomes, is simultaneously lost. Since single NFAT deficiency in T cells ameliorates GvHD in our major mismatch model, we investigated whether protection is maintained during CMV infection. Reassuringly, NFAT-deficient T cells still improved GvHD upon acute CMV infection and after allo-HCT in latently CMV-infected mice, showing reduced proinflammatory and cytotoxic potential. In sharp contrast, CMV-specific NFAT-deficient CD8+ inflated memory T cells expanded more and with higher levels of interferon gamma (IFN-γ) and GzmB expression, effectively controlling CMV. Notably, NFAT-deficient inflated memory T cells could migrate to non-lymphoid tissues and fight CMV. Therefore, CMV infection does not interfere with the protective effect of NFAT inhibition to attenuate GvHD while allowing an anti-CMV response.
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Affiliation(s)
- Nadine Hundhausen
- Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Snigdha Majumder
- Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Yin Xiao
- Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Sigrun S. Haeusl
- Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Helen Goehler
- Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Rishav Seal
- Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | | | - Andreas Rosenwald
- Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany
- Comprehensive Cancer Centre Mainfranken, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Matthias Eyrich
- Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany
| | - Luka Cicin-Sain
- Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Centre for Individualized Infection Medicine, a Joint Venture of Helmholtz Centre for Infection Research and Medical School Hannover, Hannover, Germany
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Blanco R, Muñoz JP. Human Cytomegalovirus Infection and Breast Cancer: A Literature Review of Clinical and Experimental Data. BIOLOGY 2025; 14:174. [PMID: 40001942 PMCID: PMC11851556 DOI: 10.3390/biology14020174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/05/2024] [Accepted: 12/09/2024] [Indexed: 02/27/2025]
Abstract
Breast cancer (BC) remains a significant global health challenge, highlighting the need for continued research into novel risk factors, diagnostic approaches, and personalized treatments. Among emerging risk factors, viral infections have been implicated as potential contributors to breast carcinogenesis and BC progression. Recent evidence suggests that specific oncogenic strains of human cytomegalovirus (HCMV) may have the capacity to transform human mammary epithelial cells. This review assesses clinical data regarding HCMV presence in both tumor and non-tumor breast tissues, examining the role of HCMV oncoproteins in BC development and progression. Current findings indicate a higher prevalence of HCMV infection in breast carcinomas compared to non-tumor tissues, associated with an elevated risk of BC. Additionally, the HCMV-driven breast carcinogenesis model proposed here suggests that HCMV oncoproteins may activate multiple oncogenic pathways, fostering cell proliferation, survival, and tumor development. A deeper understanding of the role of HCMV in BC could enhance risk stratification and support the creation of targeted therapeutic strategies.
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Affiliation(s)
| | - Juan P. Muñoz
- Laboratorio de Bioquímica, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile
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Sunil-Chandra NP, Jayasundara MVML, Gunathilaka MGRSS, Suminda SDH. Human cytomegalovirus (HCMV) trends in Sri Lanka: insights from a hospital-based seroprevalence analysis. BMC Infect Dis 2025; 25:184. [PMID: 39920600 PMCID: PMC11806834 DOI: 10.1186/s12879-025-10594-2] [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: 12/12/2024] [Accepted: 02/03/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Human Cytomegalovirus (HCMV) spreads through direct contact with blood, and other body fluids such as urine, saliva and breast milk. It is transmitted sexually and can also be passed from a pregnant mother to fetus via the placenta. While often asymptomatic in healthy individuals, HCMV causes symptomatic infections in immunocompromised people and congenital infections in fetuses. It is a common global congenital infection and can lead to morbidity and occasional mortality in newborns. Latent HCMV may reactivate in immunosuppressed individuals. This study aimed to determine the age and gender specific seroprevalence of HCMV in selected populations in Sri Lanka. METHODS A total of 820 blood samples obtained from 820 participants of selected low and high-risk populations in Sri Lanka, namely; hospital inpatients (n = 200), antenatal women (n = 80), blood donors (n = 80), cancer patients (n = 200), Sexually Transmitted Disease (STD) clinic attendees (n = 160) and Chronic Kidney Disease (CKD) patients on haemodialysis (n = 100) were tested for IgG antibodies against HCMV by Enzyme Linked Immunosorbent Assay (ELISA). Statistical analysis was performed using IBM SPSS Statistics version 30 (IBM® Corporation, New York, USA). RESULTS Overall HCMV seroprevalence was found to be 94.9% (778/820), whereas in males it was 95.2% (395/415) and in females it was 94.6% (383/405) (p = 0.691). Seroprevalence of HCMV in hospital inpatients, antenatal women, blood donors, cancer patients, STD clinic attendees and CKD patients on haemodialysis were found to be 92.5% (185/200), 100% (80/80), 90% (72/80), 96% (192/200), 93.1% (149/160) and 100% (100/100) respectively. Overall seroprevalence of HCMV increases with age ranging from 94.3% (33/35) in 15-19 years age group to 98.8% (84/85) in ≥ 60 years age group. CONCLUSIONS Seroprevalence of HCMV in diverse low and high-risk populations of Sri Lanka was studied for the first time. HCMV seroprevalence is similar between genders (p > 0.05) and increases with age. Over 90% of individuals are infected with HCMV by age 15, indicating a high prevalence of primary infections from early childhood to adolescence. This study provides essential background information on HCMV infection and its impacts in diverse populations of Sri Lanka and aids in executing preventive and therapeutic measures in high-risk populations.
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Affiliation(s)
- Narapity Pathirannehalage Sunil-Chandra
- Department of Medical Microbiology, Faculty of Medicine, University of Kelaniya, Ragama, 11010, Sri Lanka.
- Professor H.Y. Ranjit Perera Institute for Applied Research, Nugegoda, 10250, Sri Lanka.
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Lamara Mahammed L, Omrani Z, Bellachia N, Berkani LM, Saidani M, Djidjik R. High seroprevalence of CMV among Algerian hemodialysis patients and the general population: Intermediate-risk patients for post-transplant CMV infection. Transpl Immunol 2025; 88:102168. [PMID: 39716649 DOI: 10.1016/j.trim.2024.102168] [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: 02/21/2024] [Revised: 11/10/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024]
Abstract
INTRODUCTION Cytomegalovirus (CMV) is a virus of the herpesviridae family. CMV infection is associated with increased morbidity and mortality in immunocompromised subjects such as hemodialysis patients and transplant recipients. The aim of our study was to determine the serological status of potential kidney recipients and donors in order to assess the risk of post-transplant CMV infection and disease. PATIENTS AND METHODS We included 135 and 200 potential kidney transplant donors and recipients, respectively, who were tested for anti-CMV IgM and IgG by chemiluminescence on IMMULITE 2000 XPI®. RESULTS The prevalence of anti-CMV IgG was 95.50 % (95 % CI [92.63 %-98.37 %]) in hemodialysis patients and 96.30 % (95 % CI [93.12 %-99.48 %]) in potential kidney donors. The difference between the two groups was not significant (p = 0.721). Anti-CMV IgM were only detected in the sera of 13 hemodialysis patients and 3 healthy subjects. In both groups, the highest rate of anti-CMV IgG positivity was observed in subjects aged over 50 years (100 %), followed by those aged between 18 and 30 years old, with a slightly higher seroprevalence in men than in women. CONCLUSION Our results suggest a high prevalence of anti-CMV IgG in potential kidney donors and recipients (D+/R+), who could be classified as an intermediate risk group for post-transplant CMV infection and/or disease.
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Affiliation(s)
- Lydia Lamara Mahammed
- Department of Medical Immunology, Beni-Messous Teaching Hospital, Algiers, Algeria; Faculty of Pharmacy, University of Algiers, Algiers, Algeria.
| | - Zineb Omrani
- Faculty of Pharmacy, University of Algiers, Algiers, Algeria
| | | | - Lilya Meriem Berkani
- Department of Medical Immunology, Beni-Messous Teaching Hospital, Algiers, Algeria; Faculty of Pharmacy, University of Algiers, Algiers, Algeria
| | - Messaoud Saidani
- Department of Nephrology, Beni-Messous Teaching Hospital, Algiers, Algeria; Faculty of Medicine, University of Algiers, Algiers, Algeria
| | - Reda Djidjik
- Department of Medical Immunology, Beni-Messous Teaching Hospital, Algiers, Algeria; Faculty of Pharmacy, University of Algiers, Algiers, Algeria
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Wu PY, Kang EYC, Chen WD, Garg SJ, Chiang WY, Lee MH, Chou HD, Wang NK, Chao AN, Chen KJ, Wu WC, Hwang YS. Retinal detachment and mortality in patients with cytomegalovirus retinitis: A multicenter study in taiwan. Graefes Arch Clin Exp Ophthalmol 2025; 263:393-403. [PMID: 39422751 DOI: 10.1007/s00417-024-06651-2] [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: 08/08/2024] [Revised: 09/21/2024] [Accepted: 09/27/2024] [Indexed: 10/19/2024] Open
Abstract
PURPOSE To characterize patients with cytomegalovirus (CMV) retinitis and identify risk factors for retinal detachment (RD) and mortality in this Taiwanese patient population. METHODS This retrospective study included patients diagnosed with CMV retinitis between 2007 and 2019. The diagnosis was confirmed through aqueous polymerase chain reaction (PCR). Relevant data were collected from the Chang Gung Research Database. Univariate Cox regression was performed to identify the associations of RD and mortality risks with various patient characteristics, including demographic features, comorbidities, laboratory results, and medication use patterns. RESULTS In total, 32 patients with CMV retinitis were included. Among these patients, 78.1% had an immunocompromised status, including 56.3% with high-dose systemic steroid use, 21.9% with HIV infection, 12.5% with hematologic malignancy, and 9.4% with renal transplantation. Approximately 21.9% of patients had RD 2.4 ± 2.1 months after CMV retinitis diagnosis, and 34.4% died within 6.2 [4.2, 38.2] months after diagnosis. Patients with RD had a statistically significant, but likely not clinically significant, later initiation of anti-CMV medications compared to their non-RD counterparts (8 [5, 23] days vs. 2 [1, 11] days, p = 0.039). Mortality was significantly associated with older age (hazard ratio [HR]: 1.06; 95% confidence interval [CI]: 1.02-1.10), hematologic malignancy (HR: 5.92; 95% CI: 1.44-24.37), and positivity for CMV on blood PCR (HR: 4.93; 95% CI: 1.49-16.35). CONCLUSION Our study suggests that older age, hematologic malignancy, and positivity for CMV on blood PCR are risk factors for mortality in patients with CMV retinitis. KEY MESSAGES What is known Cytomegalovirus (CMV) retinitis is the predominant sight-threatening opportunistic ocular infection in patients with acquired immunodeficiency syndrome (AIDS). What is new In the era of highly active antiretroviral therapy for AIDS, the majority of CMV retinitis patients are those receiving immunomodulatory therapy for underlying diseases. Older age, hematologic malignancy, and positive blood polymerase chain reaction for CMV are potential risk factors for mortality in patients with CMV retinitis.
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Affiliation(s)
- Po-Yi Wu
- Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital, No. 5, Fu Shin St, Kuei-Shan, Taoyuan, 333, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Eugene Yu-Chuan Kang
- Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital, No. 5, Fu Shin St, Kuei-Shan, Taoyuan, 333, Taiwan.
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
| | - Wei-Dar Chen
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Ophthalmology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Sunir J Garg
- MidAtlantic Retina, The Retina Service of Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA
| | - Wei-Yu Chiang
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ming-Hsun Lee
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Infectious Diseases, Department of Internal Medicine, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hung-Da Chou
- Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital, No. 5, Fu Shin St, Kuei-Shan, Taoyuan, 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Nan-Kai Wang
- Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital, No. 5, Fu Shin St, Kuei-Shan, Taoyuan, 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - An-Ning Chao
- Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital, No. 5, Fu Shin St, Kuei-Shan, Taoyuan, 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kuan-Jen Chen
- Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital, No. 5, Fu Shin St, Kuei-Shan, Taoyuan, 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Chi Wu
- Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital, No. 5, Fu Shin St, Kuei-Shan, Taoyuan, 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yih-Shiou Hwang
- Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital, No. 5, Fu Shin St, Kuei-Shan, Taoyuan, 333, Taiwan.
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Department of Ophthalmology, Jen-Ai Hospital Dali Branch, Taichung, Taiwan.
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Scohy A, Argudín MA, Kabera F, Olive N, Kabamba Mukadi B. Evaluation of the Alinity m CMV assay for detecting and quantifying cytomegalovirus DNA in non-plasma samples. J Virol Methods 2025; 332:115069. [PMID: 39571937 DOI: 10.1016/j.jviromet.2024.115069] [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: 06/22/2024] [Revised: 11/06/2024] [Accepted: 11/14/2024] [Indexed: 11/26/2024]
Abstract
CMV infection remains a well-recognized threat in immunocompromised patients and is a major cause of congenital infection. If plasma and whole blood are routinely used as clinical samples for detection of CMV infection and disease, CMV laboratory testing in non-blood samples is becoming more and more relevant to support the diagnosis, prognosis and management of CMV infection. Accurate CMV viral load assessment in various body fluids is therefore essential. We evaluated the performance of the Alinity m CMV assay for detecting and quantifying CMV in plasma, amniotic fluid, bronchoalveolar lavage, cerebrospinal fluid, saliva and urine. Using a commercially available CMV reference panel and CMV culture supernatant, we assessed the linearity and accuracy of the Alinity m CMV assay across the different sample types. Excellent linear correlations (r values > 0.98) and a good accuracy (bias < ± 0.50 Log10 IU/mL and SD < 0.23) were observed. In conclusion, the Alinity m CMV assay is suitable to detect and quantify CMV DNA in plasma but also in all non-plasma samples tested. Random and continuous access capabilities of the Alinity m enable rapid and efficient laboratory detection and quantification of CMV DNA.
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Affiliation(s)
- Anaïs Scohy
- Department of Laboratory Medicine, Cliniques universitaires Saint-Luc, Brussels, Belgium; Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium.
| | - Maria A Argudín
- Department of Laboratory Medicine, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Florence Kabera
- Department of Laboratory Medicine, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Nathalie Olive
- Department of Laboratory Medicine, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Benoît Kabamba Mukadi
- Department of Laboratory Medicine, Cliniques universitaires Saint-Luc, Brussels, Belgium; Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium
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Van den Eede E, De Keersmaecker B, Lagrou K, Van der Veeken L, Vanwinkel S, Vangoitsenhoven M, Aertsen M, De Catte L. Prevalence and timing of prenatal ultrasound findings in cytomegalovirus-infected pregnancies. Acta Obstet Gynecol Scand 2025; 104:302-308. [PMID: 39618174 PMCID: PMC11782058 DOI: 10.1111/aogs.15018] [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: 07/15/2024] [Revised: 10/04/2024] [Accepted: 10/31/2024] [Indexed: 02/01/2025]
Abstract
INTRODUCTION To investigate the prevalence and timing of prenatal neurosonographic abnormalities after primary cytomegalovirus seroconversion by the first trimester of pregnancy. The additional value of magnetic resonance imaging (MRI) and the correlation between cytomegalovirus viral load in amniotic fluid and adverse neonatal outcomes were evaluated. MATERIAL AND METHODS A retrospective study between 2006 and 2022 examined data from 440 women with amniocentesis for periconceptional and first-trimester cytomegalovirus seroconversion. Cases with positive amniocentesis and subsequent follow-up were included. Prenatal neurosonography, MRI, and clinical outcomes were analyzed. RESULTS Out of 190 women included, 37% (n = 70) presented with a normal neurosonography. Patients exhibiting abnormal neurosonography findings showed higher viral loads in amniotic fluid compared to those with a normal neurosonography (p = 0.002). In 26% (n = 49) the first abnormal ultrasound sign was already picked up at amniocentesis, and the most common ones were echogenic bowels (49%) and periventricular echogenicity (43%). With increasing gestational age, the likelihood of a new abnormal neurosonography finding decreases. MRI discovered additional abnormalities in 14% (n = 10). CONCLUSIONS The results highlight the importance of combining diagnostic modalities, from amniocentesis to biweekly ultrasound monitoring and subsequent MRI evaluation, to capture the chronological progression and subsequent outcome of congenital cytomegalovirus.
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Affiliation(s)
- Emma Van den Eede
- Department of Development and RegenerationBiomedical Sciences KU LeuvenLeuvenBelgium
- Department of Obstetrics and GynecologyUniversity Hospitals LeuvenLeuvenBelgium
- Department of Obstetrics and GynecologyUniversity Hospital AntwerpAntwerpBelgium
| | - Bart De Keersmaecker
- Department of Development and RegenerationBiomedical Sciences KU LeuvenLeuvenBelgium
- Department of Obstetrics and GynecologyUniversity Hospitals LeuvenLeuvenBelgium
- Department of Obstetrics and GynecologyAZ GroeningeKortrijkBelgium
| | - Katrien Lagrou
- Department of Laboratory MedicineUZ LeuvenLeuvenBelgium
- Department of MicrobiologyImmunology and Transplantation, KU LeuvenLeuvenBelgium
| | - Lennart Van der Veeken
- Department of Development and RegenerationBiomedical Sciences KU LeuvenLeuvenBelgium
- Department of Obstetrics and GynecologyUniversity Hospitals LeuvenLeuvenBelgium
- Department of Obstetrics and GynecologyUniversity Hospital AntwerpAntwerpBelgium
| | - Sanne Vanwinkel
- Department of Obstetrics and GynecologyUniversity Hospitals LeuvenLeuvenBelgium
| | | | - Michael Aertsen
- Department of RadiologyUniversity Hospital LeuvenLeuvenBelgium
- Department of Imaging and PathologyBiomedical Sciences, KU LeuvenLeuvenBelgium
| | - Luc De Catte
- Department of Development and RegenerationBiomedical Sciences KU LeuvenLeuvenBelgium
- Department of Obstetrics and GynecologyUniversity Hospitals LeuvenLeuvenBelgium
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D'Costa J, Chibo D, Soloczynskyj K, Batty M, Sameer R, Lee E, Tran T, Mavroulis D, Gooey M, Williams E, Jackson K. Evaluation and comparison of three high throughput assays (Alinity m CMV, Aptima CMV Quant and cobas CMV) for quantifying CMV DNA in plasma samples. J Virol Methods 2025; 332:115068. [PMID: 39551443 DOI: 10.1016/j.jviromet.2024.115068] [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: 06/16/2024] [Revised: 10/23/2024] [Accepted: 11/14/2024] [Indexed: 11/19/2024]
Abstract
BACKGROUND Cytomegalovirus (CMV) can cause symptomatic CMV syndrome or tissue-invasive CMV disease in immunocompromised individuals, including solid-organ transplant and hematopoietic stem cell transplant recipients. In these populations, monitoring of CMV load is essential, assessing both risk of disease and response to antiviral therapy. High throughput commercial assays are currently available for CMV quantitation, but they are often evaluated independently, with few studies comparing these assays. This study evaluated CMV quantitative assays for use with the Roche cobas 6800, Abbott Alinity m and Hologic Panther platforms using stored patient plasma. METHODS Analytical evaluation was performed using the 1st WHO international standard for human CMV for Nucleic Acid Amplification Techniques (cobas and Alinity m) or the Hologic CMV QC Calibrator 6 (Aptima). Parallel testing of 136 clinical plasma samples was performed across the three platforms. RESULTS Linearity for each assay ranged from 98.6 % to 99.96 % and precision and limit of quantitation were as expected with little variation between platforms. 136 clinical plasma samples were evaluated with similar agreement observed between each assay. The greatest positive agreement was between the Aptima Quant and Alinity m assays (95.6 %, 95 % CI 89-98.6 %) and the lowest between the Aptima Quant and cobas assays (94.1 %, 87.4-97.5 %). CONCLUSIONS All assays were sensitive and accurate when quantifying CMV, and performance across all 3 assays was comparable for monitoring CMV viral loads in patient plasma.
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Affiliation(s)
- Jodie D'Costa
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia.
| | - Doris Chibo
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Katherine Soloczynskyj
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Mitchell Batty
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Rizmina Sameer
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Elaine Lee
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Thomas Tran
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Dimi Mavroulis
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Megan Gooey
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Eloise Williams
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
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Chung MC, Chen CH, Chang SS, Lee CY, Tian YC, Wu MY, Wang HH, Yu CC, Chen TW, Kao CC, Hsu CY, Chiang YJ, Wu MJ, Chen YT, Wu MS. Prevention and management of cytomegalovirus infection and disease in kidney transplant: A consensus statement of the Transplantation Society of Taiwan. J Formos Med Assoc 2025; 124:104-111. [PMID: 38777672 DOI: 10.1016/j.jfma.2024.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/24/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
Kidney transplant recipients have an increased risk of cytomegalovirus (CMV) infection and disease. A strategy for mitigating the risk of CMV infection in kidney transplant recipients has not yet been established in Taiwan. The Transplantation Society of Taiwan aimed to develop a consensus by expert opinion on the prevention and management of CMV infection. Based on the results of Consensus Conference, we suggested low-dose valganciclovir prophylaxis (450 mg once daily) for kidney transplant recipients. The prophylaxis duration was ≥6 months for high-risk (D+/R-) patients and 3 months for moderate-risk (R+) patients. Even for low-risk (D-/R-) patients, prophylaxis for at least 3 months is recommended because of the high seroprevalence of CMV in Taiwan. CMV prophylaxis was suggested after anti-thymocyte globulin treatment but not after methylprednisolone pulse therapy. Routine surveillance after prophylaxis, secondary prophylaxis after CMV disease treatment, and mTOR inhibitors for primary CMV prophylaxis were not recommended. Letermovir and marabavir are emerging CMV agents used for prophylaxis and refractory CMV disease. CMV immunoglobulins have been used to treat refractory CMV disease in Taiwan. We hope this consensus will help professionals manage patients with CMV in Taiwan to improve the quality of care.
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Affiliation(s)
- Mu-Chi Chung
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taiwan; Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Cheng-Hsu Chen
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taiwan; Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Ph.D. Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; Department of Life Science, Tunghai University, Taichung, Taiwan
| | - Shen-Shin Chang
- Division of Transplantation, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Yuan Lee
- Department of Surgery, National Taiwan University Hospital, Taiwan
| | - Ya-Chung Tian
- Kidney Research Center and Department of Nephrology Linkou Chang Aging Memorial Hospital, Taiwan
| | - Mei-Yi Wu
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
| | - Hsu-Han Wang
- Department of Urology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chia-Cheng Yu
- Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Teng-Wei Chen
- Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chien-Chang Kao
- Division of Urology, Department of Surgery, Tri-service General Hospital, National Defense Medical, Taiwan
| | - Chih-Yang Hsu
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Taiwan
| | - Yang-Jen Chiang
- Department of Urology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ming-Ju Wu
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taiwan; Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yen-Ta Chen
- Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Mai-Szu Wu
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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Xu X, Silveira A, Lundman P, Rahbar A, Söderberg-Nauclér C. Enhanced levels of IL-6 and PAI-1 and decreased levels of MMP-3 in cytomegalovirus seropositive patients with prior myocardial infarction. IJC HEART & VASCULATURE 2025; 56:101570. [PMID: 39691830 PMCID: PMC11650320 DOI: 10.1016/j.ijcha.2024.101570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/10/2024] [Accepted: 11/22/2024] [Indexed: 12/19/2024]
Abstract
Background Efforts to understand atherosclerosis, a major cause of ischemic heart disease, have linked several lifestyle factors to increased risk for developing cardiovascular disease. Some studies suggest that cytomegalovirus (CMV), a widely prevalent herpesvirus, is reactivated in atherosclerotic plaques and associated with higher cardiovascular mortality risk. We aimed to explore whether CMV seropositivity and CMV-IgG antibody levels correlate with relevant biomarkers in a cohort of patients with myocardial infarction (MI) and matched controls. Methods and results We analyzed a dataset from 324 survivors of MI treated in Stockholm between 1996 and 2001. Blood samples collected three months after MI were used to measure protective Apo B100 autoantibodies, metabolic, and inflammatory biomarkers. CMV serology was performed on stored serum samples. Correlation analyses were conducted between biomarkers and CMV serostatus in 324 patients and age- and sex-matched controls. While CMV seroprevalence was equal, the CMV-IgG levels were higher in controls. Among various factors examined, CMV seropositive MI patients had elevated levels of plasminogen activator inhibitor-1 (PAI-1) and interleukin-6, along with lower levels of MMP-3, than CMV seronegative MI patients. CMV-IgG levels correlated positively with PAI-1 levels in patients. Although CMV seropositivity was associated with increased proinsulin levels, there was no correlation with diabetes diagnosis. Conclusions Our findings suggest an enhanced inflammatory and prothrombotic state in CMV seropositive patients after MI. Notably, patients had lower levels of CMV IgG than controls.
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Affiliation(s)
- Xinling Xu
- Department of Medicine Solna, Unit Microbial Pathogenesis, Karolinska Institutet, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Angela Silveira
- Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Pia Lundman
- Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden
| | - Afsar Rahbar
- Department of Medicine Solna, Unit Microbial Pathogenesis, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Cecilia Söderberg-Nauclér
- Department of Medicine Solna, Unit Microbial Pathogenesis, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Neurology, Karolinska University Hospital, Stockholm, Sweden
- Department of Biosciences, InFLAMES Research Flagship Center, MediCity, University of Turku, Finland
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Desu H, Balthazard R, Daigneault A, Da Cal S, Klément W, Yu J, Clénet ML, Margarido C, Levert A, Fantodji C, Tastet O, Girard JM, Duquette P, Prat A, Macaron G, Rousseau MC, Arbour N, Larochelle C. Peripheral blood age-sensitive immune markers in multiple sclerosis: relation to sex, cytomegalovirus status, and treatment. EBioMedicine 2025; 112:105559. [PMID: 39837012 PMCID: PMC11788784 DOI: 10.1016/j.ebiom.2025.105559] [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: 08/14/2024] [Revised: 12/17/2024] [Accepted: 01/06/2025] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND Immunosenescence is accelerated by chronic infectious and autoimmune diseases and could contribute to the pathobiology of multiple sclerosis (MS). How MS and disease-modifying therapies (DMTs) impact age-sensitive immune biomarkers is only partially understood. METHODS We analyzed 771 serum samples from 147 healthy controls and 289 people with MS (PwMS) by multiplex immunoassays. We determined cytomegalovirus (CMV) serostatus and collected retrospective clinical information. We performed unsupervised and multivariable analyses. FINDINGS Unsupervised analyses revealed that MS immune profile was characterized by low relative levels of anti-inflammatory/neuroprotective factors IL-4, IL-10, TNF, and β-NGF but high levels of growth factors EGF and bFGF. Serum levels of IL-4, β-NGF, IL-27, BDNF, and leptin were significantly influenced by sex and/or CMV status. IL-4 and β-NGF levels were lower in untreated PwMS compared to controls, while EGF and bFGF levels were influenced by age and markedly elevated in PwMS in multivariable analysis. Samples from treated PwMS, but not untreated PwMS, showed lower levels of BDNF and TNF than controls. Initiation of high efficacy DMTs, but not low efficacy DMTs, was associated with reduced levels of bFGF and EGF. Samples associated with distinct DMTs exhibited specific profiles for age-sensitive immune markers. Finally, lower levels of IL-6, TNF, IL-10, and β-NGF were observed at baseline in PwMS who subsequently experienced clinical failure after DMTs initiation. INTERPRETATION Age, sex, CMV status, and specific DMTs significantly influence levels of age-sensitive immune biomarkers associated with MS and must be considered when investigating inflammation-related biomarkers. FUNDING This work was supported by a Grant for Multiple Sclerosis Innovation by Merck KGaA (ID: 10.12039/100009945).
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Affiliation(s)
- Haritha Desu
- Department of Neurosciences, Université de Montréal, Montréal, H3T 1J4, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada
| | - Renaud Balthazard
- Department of Neurosciences, Université de Montréal, Montréal, H3T 1J4, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada
| | - Audrey Daigneault
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada
| | - Sandra Da Cal
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada
| | - Wendy Klément
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada
| | - Jennifer Yu
- Armand-Frappier Santé Biotechnologie Research Centre, Institut National de la Recherche Scientifique (INRS), Laval, H7V 1B7, Canada
| | - Marie-Laure Clénet
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada
| | - Clara Margarido
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada
| | - Annie Levert
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada
| | - Canisius Fantodji
- Armand-Frappier Santé Biotechnologie Research Centre, Institut National de la Recherche Scientifique (INRS), Laval, H7V 1B7, Canada
| | - Olivier Tastet
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada
| | - Jean-Marc Girard
- Department of Neurosciences, Université de Montréal, Montréal, H3T 1J4, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada; Multiple Sclerosis Clinic of the Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, H2X 0C1, Canada
| | - Pierre Duquette
- Department of Neurosciences, Université de Montréal, Montréal, H3T 1J4, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada; Multiple Sclerosis Clinic of the Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, H2X 0C1, Canada
| | - Alexandre Prat
- Department of Neurosciences, Université de Montréal, Montréal, H3T 1J4, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada; Multiple Sclerosis Clinic of the Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, H2X 0C1, Canada
| | - Gabrielle Macaron
- Department of Neurosciences, Université de Montréal, Montréal, H3T 1J4, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada; Multiple Sclerosis Clinic of the Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, H2X 0C1, Canada
| | - Marie-Claude Rousseau
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada; Armand-Frappier Santé Biotechnologie Research Centre, Institut National de la Recherche Scientifique (INRS), Laval, H7V 1B7, Canada; School of Public Health, Université de Montréal, Montreal, H3N 1X9, Canada
| | - Nathalie Arbour
- Department of Neurosciences, Université de Montréal, Montréal, H3T 1J4, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada.
| | - Catherine Larochelle
- Department of Neurosciences, Université de Montréal, Montréal, H3T 1J4, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, Canada; Multiple Sclerosis Clinic of the Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, H2X 0C1, Canada.
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48
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Zhang SQ, Thomas F, Fang J, Austgen K, Cowan C, Welstead GG. Universal protection of allogeneic T-cell therapies from natural killer cells via CD300a agonism. Blood Adv 2025; 9:254-264. [PMID: 39368806 PMCID: PMC11782830 DOI: 10.1182/bloodadvances.2024013436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 10/07/2024] Open
Abstract
ABSTRACT Immunogenicity limits the persistence of off-the-shelf allogeneic cell therapies and transplants. Although ablation of HLA removes most T cell and humoral alloreactivity, no solution has enabled universal protection against the resulting natural killer (NK) cell response. Here, we engineered trans-antigen signaling receptors (TASRs) as a new class of NK inhibitory ligands and discovered CD300a, a previously inaccessible receptor, as a functional target. CD300a TASR outperformed leading alternative strategies in focused screens, including CD47 and HLA-E, and was solely capable of universally protecting allogeneic T cells against a large human cohort (45/45 donors), spanning diverse demographics and NK cell phenotypes. A model allogeneic T-cell therapy coexpressing an anti-CD19 chimeric antigen receptor and CD300a TASR, produced using multiplexed nonviral integration, exhibited enhanced B-cell killing potency under allogeneic immune pressure. CD300 TASR represents a universal solution to NK alloreactivity, broadening the population that could be effectively treated by next-generation allogeneic cell therapies.
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Affiliation(s)
- Shu-Qi Zhang
- Department of Discovery Biology, Clade Therapeutics, Inc, Boston, MA
- Department of Molecular Immunology, Clade Therapeutics, Inc, Boston, MA
| | - Faith Thomas
- Department of Discovery Biology, Clade Therapeutics, Inc, Boston, MA
| | - Justin Fang
- Department of Discovery Biology, Clade Therapeutics, Inc, Boston, MA
- Department of Discovery Biology, Century Therapeutics, Inc, Boston, MA
- Department of Molecular Immunology, Clade Therapeutics, Inc, Boston, MA
| | - Kathryn Austgen
- Department of Molecular Immunology, Clade Therapeutics, Inc, Boston, MA
| | - Chad Cowan
- Clade Therapeutics, Inc, Boston, MA
- Century Therapeutics, Inc, Philadelphia, PA
| | - G. Grant Welstead
- Department of Discovery Biology, Clade Therapeutics, Inc, Boston, MA
- Department of Discovery Biology, Century Therapeutics, Inc, Boston, MA
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Chiavarini M, Genga A, Ricciotti GM, D’Errico MM, Barbadoro P. Safety, Immunogenicity, and Efficacy of Cytomegalovirus Vaccines: A Systematic Review of Randomized Controlled Trials. Vaccines (Basel) 2025; 13:85. [PMID: 39852864 PMCID: PMC11768780 DOI: 10.3390/vaccines13010085] [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: 11/29/2024] [Revised: 01/10/2025] [Accepted: 01/15/2025] [Indexed: 01/26/2025] Open
Abstract
Background/Objectives: Cytomegalovirus (CMV) is widespread and mostly causes asymptomatic infections in immunocompetent hosts, but it may lead to severe and life-threatening diseases in immunocompromised individuals, such as transplant patients and congenitally infected children, representing a significant public health concern. Although there are no licensed CMV vaccines, the development of a CMV vaccine is considered a high priority due to its potential to reduce the burden associated with CMV-related complications, and several approaches are under investigation. The objective of this systematic review was to synthesize the evidence on various CMV vaccines currently under clinical development. Methods: According to the PRISMA guidelines (PROSPERO ID: CRD42024516601), a comprehensive literature search was conducted to identify all the randomized controlled trials that have evaluated the safety, immunogenicity, and efficacy of vaccine candidates compared to a placebo. A total of 26 studies were identified: 11 on transplant patients and 15 on healthy individuals. Results: Several vaccine candidates have shown encouraging results in terms of safety and specific immune responses, notably adjuvanted gB vaccines and DNA vaccines targeting gB and pp65. The results were divided into RCTs on healthy individuals and those on transplant recipients, because the CMV-specific immune response to a vaccine is complex and varies depending not only on the type of vaccine, but also on the immunological status of the individual. Conclusions: Challenges remain in achieving broad efficacy across diverse populations, particularly for immunocompromised patients. Thus, the present work seeks to support future decisions and guide further research in the development of an effective and widely available CMV vaccine.
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Affiliation(s)
- Manuela Chiavarini
- Department of Health Sciences, University of Florence, Viale GB Morgagni 48, 50134 Florence, Italy;
| | - Anita Genga
- Department of Biomedical Sciences and Public Health, Section of Hygiene, Preventive Medicine and Public Health, Polytechnic University of the Marche Region, 60126 Ancona, Italy; (M.M.D.); (P.B.)
| | - Giorgia Maria Ricciotti
- Department of Biomedical Sciences and Public Health, Section of Hygiene, Preventive Medicine and Public Health, Polytechnic University of the Marche Region, 60126 Ancona, Italy; (M.M.D.); (P.B.)
| | - Marcello Mario D’Errico
- Department of Biomedical Sciences and Public Health, Section of Hygiene, Preventive Medicine and Public Health, Polytechnic University of the Marche Region, 60126 Ancona, Italy; (M.M.D.); (P.B.)
| | - Pamela Barbadoro
- Department of Biomedical Sciences and Public Health, Section of Hygiene, Preventive Medicine and Public Health, Polytechnic University of the Marche Region, 60126 Ancona, Italy; (M.M.D.); (P.B.)
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50
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Neugebauer E, Walter S, Tan J, Drayman N, Franke V, van Gent M, Pennisi S, Veratti P, Stein KS, Welker I, Tay S, Verjans GMGM, Timmers HTM, Akalin A, Landthaler M, Ensser A, Wyler E, Full F. Herpesviruses mimic zygotic genome activation to promote viral replication. Nat Commun 2025; 16:710. [PMID: 39814710 PMCID: PMC11735616 DOI: 10.1038/s41467-025-55928-5] [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: 10/16/2024] [Accepted: 01/05/2025] [Indexed: 01/18/2025] Open
Abstract
Zygotic genome activation (ZGA) is crucial for maternal to zygotic transition at the 2-8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In humans, ZGA is induced by DUX4, a pioneer factor that drives expression of downstream germline-specific genes and retroelements. Here we show that herpesviruses from all subfamilies, papillomaviruses and Merkel cell polyomavirus actively induce DUX4 expression to promote viral transcription and replication. Analysis of single-cell sequencing data sets from patients shows that viral DUX4 activation is of relevance in vivo. Herpes-simplex virus 1 (HSV-1) immediate early proteins directly induce expression of DUX4 and its target genes, which mimics zygotic genome activation. Upon HSV-1 infection, DUX4 directly binds to the viral genome and promotes viral transcription. DUX4 is functionally required for infection, since genetic depletion by CRISPR/Cas9 as well as degradation of DUX4 by nanobody constructs abrogates HSV-1 replication. Our results show that DNA viruses including herpesviruses mimic an embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression.
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Affiliation(s)
- Eva Neugebauer
- Institute of Virology, University Medical Center, and Faculty of Medicine, Albert-Ludwig-University Freiburg, Freiburg, Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Stephanie Walter
- Institute for Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Jiang Tan
- Institute of Virology, University Medical Center, and Faculty of Medicine, Albert-Ludwig-University Freiburg, Freiburg, Germany
| | - Nir Drayman
- The Department of Molecular Biology and Biochemistry, the Center for Virus Research and the Center for Complex Biological Systems, The University of California, Irvine, Irvine, CA, 92697, USA
| | - Vedran Franke
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Helmholtz Society, Berlin, Germany
| | - Michiel van Gent
- HerpesLabNL, Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Sandra Pennisi
- Institute of Virology, University Medical Center, and Faculty of Medicine, Albert-Ludwig-University Freiburg, Freiburg, Germany
| | - Pia Veratti
- Institute of Virology, University Medical Center, and Faculty of Medicine, Albert-Ludwig-University Freiburg, Freiburg, Germany
| | - Karla S Stein
- Institute of Virology, University Medical Center, and Faculty of Medicine, Albert-Ludwig-University Freiburg, Freiburg, Germany
| | - Isabelle Welker
- Institute of Virology, University Medical Center, and Faculty of Medicine, Albert-Ludwig-University Freiburg, Freiburg, Germany
| | - Savaş Tay
- The Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, 60637, USA
| | - Georges M G M Verjans
- HerpesLabNL, Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands
| | - H T Marc Timmers
- German Cancer Consortium (DKTK), partner site Freiburg, a partnership between the DKFZ and Medical Center-University of Freiburg, and Department of Urology, Medical Center-University of Freiburg, Freiburg, Germany
| | - Altuna Akalin
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Helmholtz Society, Berlin, Germany
| | - Markus Landthaler
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Helmholtz Society, Berlin, Germany
| | - Armin Ensser
- Institute for Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Emanuel Wyler
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Helmholtz Society, Berlin, Germany
| | - Florian Full
- Institute of Virology, University Medical Center, and Faculty of Medicine, Albert-Ludwig-University Freiburg, Freiburg, Germany.
- German Consulting Laboratory for HSV and VZV, Medical Center - University of Freiburg, Freiburg, Germany.
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