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Search Results (456)

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Keywords = innate immunity to COVID-19

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19 pages, 2770 KB  
Article
Strain-Specific Variability in Viral Kinetics, Cytokine Response, and Cellular Damage in Air–Liquid Cultures of Human Nasal Organoids After Infection with SARS-CoV-2
by Gina M. Aloisio, Trevor J. McBride, Letisha Aideyan, Emily M. Schultz, Ashley M. Murray, Anubama Rajan, Erin G. Nicholson, David Henke, Laura Ferlic-Stark, Amal Kambal, Hannah L. Johnson, Elina A. Mosa, Fabio Stossi, Sarah E. Blutt, Pedro A. Piedra and Vasanthi Avadhanula
Viruses 2025, 17(10), 1343; https://doi.org/10.3390/v17101343 - 6 Oct 2025
Viewed by 54
Abstract
SARS-CoV-2 variants have demonstrated distinct epidemiological patterns and clinical presentations throughout the COVID-19 pandemic. Understanding variant-specific differences at the respiratory epithelium is crucial for understanding their pathogenesis. Here, we utilized human nasal organoid air–liquid interface (HNO-ALI) cell cultures to compare the viral replication [...] Read more.
SARS-CoV-2 variants have demonstrated distinct epidemiological patterns and clinical presentations throughout the COVID-19 pandemic. Understanding variant-specific differences at the respiratory epithelium is crucial for understanding their pathogenesis. Here, we utilized human nasal organoid air–liquid interface (HNO-ALI) cell cultures to compare the viral replication kinetics, innate immune response, and epithelial damage of six different strains of SARS-CoV-2 (B.1.2, WA, Alpha, Beta, Delta, and Omicron). All variants replicated efficiently in HNO-ALIs, but with distinct replication kinetic patterns. The Delta variant exhibited delayed replication kinetics, achieving a steady state at 6 days post-infection compared to 3 days for other variants. Cytokine analysis revealed robust pro-inflammatory and chemoattractant responses (IL-6, IL-8, IP-10, CXCL9, and CXCL11) in WA1, Alpha, Beta, and Omicron infections, while Delta significantly dampened the innate immune response, with no significant induction of IL-6, IP-10, CXCL9, or CXCL11. Immunofluorescence and H&E analysis showed that all variants caused significant ciliary damage, though WA1 and Delta demonstrated less destruction at early time points (3 days post-infection). Together, these data show that, in our HNO-ALI model, the Delta variant employs a distinct “stealth” strategy characterized by delayed replication kinetics and epithelial cell innate immune evasion when compared to other variants of SARS-CoV-2, potentially explaining a mechanism that the Delta variant can use for its enhanced transmissibility and virulence observed clinically. Our findings demonstrate that variant-specific differences at the respiratory epithelium could explain some of the distinct clinical presentations and highlight the utility of the HNO-ALI system for the rapid assessment of emerging variants. Full article
(This article belongs to the Special Issue Viral Infection in Airway Epithelial Cells)
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15 pages, 908 KB  
Review
A Targeted Blockade of Terminal C5a Is Critical to Management of Sepsis and Acute Respiratory Distress Syndrome: The Mechanism of Action of Vilobelimab
by Matthew W. McCarthy, Camilla Chong, Niels C. Riedemann and Renfeng Guo
Int. J. Mol. Sci. 2025, 26(19), 9628; https://doi.org/10.3390/ijms26199628 - 2 Oct 2025
Viewed by 367
Abstract
Vilobelimab, a first-in-class, human–mouse chimeric immunoglobulin G4 (IgG4) kappa monoclonal antibody, targets human complement component 5a (C5a) in plasma. Unlike upstream complement inhibitors, vilobelimab does not inhibit the generation of the membrane attack complex (C5b-9), necessary to mitigate certain infections. C5a is a [...] Read more.
Vilobelimab, a first-in-class, human–mouse chimeric immunoglobulin G4 (IgG4) kappa monoclonal antibody, targets human complement component 5a (C5a) in plasma. Unlike upstream complement inhibitors, vilobelimab does not inhibit the generation of the membrane attack complex (C5b-9), necessary to mitigate certain infections. C5a is a strong anaphylatoxin and chemotactic agent that plays an essential role in both innate and adaptive immunity. Elevated levels of C5a have been associated with pathologic processes, including sepsis and inflammatory respiratory disorders such as acute respiratory distress syndrome (ARDS). Blocking C5a with vilobelimab has shown therapeutic promise. A randomized, multicenter placebo-controlled Phase III study of vilobelimab in patients with severe COVID-19 (PANAMO) found that patients treated with vilobelimab had a significantly lower risk of death by day 28 and 60. Based on this study, the United States Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Gohibic® (vilobelimab) injection for the treatment of COVID-19 in hospitalized adults when initiated within 48 h of receiving invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). In January 2025, the European Commission (EC) granted marketing authorization for Gohibic® (vilobelimab) for the treatment of adult patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced ARDS who are receiving systemic corticosteroids as part of standard of care and receiving IMV with or without ECMO. Herein, we review the mechanism of action of vilobelimab in selectively inhibiting C5a-induced inflammation, outlining its bench-to-bedside development from the fundamental biology of the complement system and preclinical evidence through to the clinical data demonstrating its life-saving potential in the management of COVID-19–induced ARDS. Full article
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13 pages, 2468 KB  
Article
Long COVID and Type I IFN Signature in Working-Age Adults: A Cross-Sectional Study
by Letizia Santinelli, Elio Gentilini Cacciola, Luca Bortolani, Marco Ridolfi, Luca Maddaloni, Federica Frasca, Matteo Fracella, Ginevra Bugani, Gabriella d’Ettorre, Claudio M. Mastroianni, Giancarlo Ceccarelli and Gabriele d’Ettorre
Int. J. Mol. Sci. 2025, 26(18), 9089; https://doi.org/10.3390/ijms26189089 - 18 Sep 2025
Viewed by 321
Abstract
To investigate relevant biomarkers that might aid in the diagnosis and monitoring of long COVID (LC), an analysis of IFN-α, IFN-β, ISG15, and ISG56 transcripts was performed by Real-Time PCR among people of working age who had been infected with SARS-CoV-2 one year [...] Read more.
To investigate relevant biomarkers that might aid in the diagnosis and monitoring of long COVID (LC), an analysis of IFN-α, IFN-β, ISG15, and ISG56 transcripts was performed by Real-Time PCR among people of working age who had been infected with SARS-CoV-2 one year prior to the study [LC and non-long COVID (NLC)]. Despite no differences in the transcript levels of IFN-α, IFN-β, ISG15, and ISG56 between LC and NLC, higher IFN-β mRNA levels were observed among LC compared to NLC individuals who were hospitalized for more than 10 days during acute SARS-CoV-2 infection. Moreover, previously SARS-CoV-2 infected participants that did not require respiratory support and developed LC exhibited higher levels of IFN-α and IFN-β compared to NLC with the same clinical characteristics. These results highlight that SARS-CoV-2 infection leads to changes in peripheral innate immune pathways, which could have implications for the development of LC. Full article
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34 pages, 1750 KB  
Review
Pattern Recognition Receptors (PRRs) Expression and Activation in COVID-19 and Long COVID: From SARS-CoV-2 Escape Mechanisms to Emerging PRR-Targeted Immunotherapies
by Luca Maddaloni, Ginevra Bugani, Matteo Fracella, Camilla Bitossi, Alessandra D’Auria, Francesca Aloisi, Abir Azri, Letizia Santinelli, Manel Ben M’Hadheb, Alessandra Pierangeli, Federica Frasca and Carolina Scagnolari
Microorganisms 2025, 13(9), 2176; https://doi.org/10.3390/microorganisms13092176 - 17 Sep 2025
Viewed by 557
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recognized by pattern recognition receptors (PRRs), which play a vital role in triggering innate immune responses such as the production of type I and III interferons (IFNs). While modest PRR activation helps to defend against [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recognized by pattern recognition receptors (PRRs), which play a vital role in triggering innate immune responses such as the production of type I and III interferons (IFNs). While modest PRR activation helps to defend against SARS-CoV-2, excessive or sustained activation can cause harmful inflammation and contribute to severe Coronavirus Disease 2019 (COVID-19). Altered expression of Toll-like receptors (TLRs), which are among the most important members of the PRR family members, particularly TLRs 2, 3, 4, 7, 8 and 9, has been strongly linked to COVID-19 severity. Furthermore, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), collectively known as RLRs (RIG-I-like receptors), act as sensors that detect SARS-CoV-2 RNA. The expression of these receptors, as well as that of different DNA sensors, varies in patients infected with SARS-CoV-2. Changes in PRR expression, particularly that of TLRs, cyclic GMP-AMP synthase (cGAS), and the stimulator of interferon genes (STING), have also been shown to play a role in the development and persistence of long COVID (LC). However, SARS-CoV-2 has evolved strategies to evade PRR recognition and subsequent signaling pathway activation, contributing to the IFN response dysregulation observed in SARS-CoV-2-infected patients. Nevertheless, PRR agonists and antagonists remain promising therapeutic targets for SARS-CoV-2 infection. This review aims to describe the PRRs involved in recognizing SARS-CoV-2, explore their expression during SARS-CoV-2 infection, and examine their role in determining the severity of both COVID-19 and long-term manifestations of the disease. It also describes the strategies developed by SARS-CoV-2 to evade PRR recognition and activation. Moreover, given the considerable interest in modulating PRR activity as a novel immunotherapy approach, this review will provide a description of PRR agonists and antagonists that have been investigated as antiviral strategies against SARS-CoV-2. This review aims to explore the complex interplay between PRRs and SARS-CoV-2 in depth, considering its implications for prognostic biomarkers, targeted therapeutic strategies and the mechanistic understanding of long LC. Additionally, it outlines future perspectives that could help to address knowledge gaps in PRR-mediated responses during SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Immunity and Viral Immune Evasion Strategies: Recent Insights)
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42 pages, 1810 KB  
Review
Reactive Sulfur Species and Protein Persulfidation: An Emerging Redox Axis in Human Health and Disease
by Celia María Curieses Andrés, Fernando Lobo, José Manuel Pérez de la Lastra, Elena Bustamante Munguira, Celia Andrés Juan and Eduardo Pérez Lebeña
Curr. Issues Mol. Biol. 2025, 47(9), 765; https://doi.org/10.3390/cimb47090765 - 16 Sep 2025
Viewed by 600
Abstract
Reactive sulfur species (RSS)—hydrogen sulfide (H2S), low-molecular-weight persulfides/polysulfides and protein persulfidation—constitute a third redox axis alongside ROS and RNS. Nanomolar H2S, produced by trans-sulfuration (CBS/CSE) and 3-MST, is oxidized by sulfide–quinone reductase to persulfides that fuel the respiratory chain [...] Read more.
Reactive sulfur species (RSS)—hydrogen sulfide (H2S), low-molecular-weight persulfides/polysulfides and protein persulfidation—constitute a third redox axis alongside ROS and RNS. Nanomolar H2S, produced by trans-sulfuration (CBS/CSE) and 3-MST, is oxidized by sulfide–quinone reductase to persulfides that fuel the respiratory chain while curbing superoxide. Reversible persulfidation reprograms cysteine sensors in metabolism (GAPDH), inflammation (NLRP3, p47phox) and transcription (Keap1/NRF2), linking RSS to energy balance, vasodilation, innate immunity and neuroplasticity. Disrupted sulfur signaling—deficit or overload—contributes to heart failure, sarcopenia, neurodegeneration, cancer and post-COVID syndromes. Therapeutically, slow-release donors (SG1002, GYY4137), mitochondria-targeted vectors (AP39), photo- or thiol-activated “smart” scaffolds, diet-derived polysulfides/isothiocyanates and microbiota engineering aim to restore the protective RSS window. Key challenges are a narrow therapeutic margin and real-time quantification of persulfide fluxes. Harnessing RSS therefore offers a route to rebalance redox homeostasis across diverse chronic diseases. Full article
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17 pages, 1008 KB  
Article
Impact of COVID-19 on Mucosal Immunity and Antibody Responses in COVID Vaccinees
by Priya Kannian, Muruganantham Lillimary Eniya, Pasuvaraj Mahanathi, Arul Gracemary, Nagalingeswaran Kumarasamy and Stephen J. Challacombe
Vaccines 2025, 13(9), 967; https://doi.org/10.3390/vaccines13090967 - 12 Sep 2025
Viewed by 600
Abstract
Background and Objectives: SARS-CoV-2 infection initiates at mucosal surfaces, and mucosal immunity may influence the nature and severity of infection. Little is known about the induction of mucosal immunity by vaccination in COVID-19 convalescents. Methods: Sera from 205 healthcare workers were [...] Read more.
Background and Objectives: SARS-CoV-2 infection initiates at mucosal surfaces, and mucosal immunity may influence the nature and severity of infection. Little is known about the induction of mucosal immunity by vaccination in COVID-19 convalescents. Methods: Sera from 205 healthcare workers were collected one month after the first Covishield vaccination and 1/3/6 months after the second vaccination, while paired sera and stimulated whole-mouth fluid (SWMF) was collected 1/3/6 months after the third vaccination (N = 10) and at 0/30/90 days after a COVID-19 episode (N = 8). Anti-SARS-CoV-2 spike antibody detection by ECLIA/ELISA and cytokine detection by ELISA/CBA were performed. Results: One month post-second vaccination, serum antibodies had increased significantly (6-fold) in the COVID-19-naïve group (CNG) but declined (1.5-fold) in the previously COVID-19-exposed group (CEG), who already had high antibody titres. The serum regulatory cytokine IL-10 levels were higher after three antigen exposures (p = 0.0002). New infections (breakthrough infections—BTIs) or reinfections (RIs) with asymptomatic/mild disease occurred in 44% of the CNG and 27% of the CEG (p < 0.01). The mucosal cytokine IL-17 levels were significantly higher in the CEG. Salivary IgG/IgA and secretory IgA antibodies were detectable both after vaccination and COVID-19. Innate cytokines (MIG, MCP-1, IL-8, IL-1β) were higher and sustained in SWMF in contrast to serum. Conclusions: Two vaccinations in the CNG resulted in an antibody boost, but the second vaccination in the CEG induced antibody anergy. Serum/mucosal antibodies declined by six months after vaccination, but the rapid increase at subsequent exposures were indicative of a good T cell/B cell memory response to SARS-CoV-2. A higher percentage of BTI among the CNG than RI among the CEG may indicate better protection due to higher antibody responses in the latter group. Full article
(This article belongs to the Special Issue A One-Health Perspective on Immunization Against Infectious Diseases)
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15 pages, 647 KB  
Review
Hypochlorous Acid (HOCl) as a Promising Respiratory Antiseptic
by Michael Winter, Dirk Boecker and Wilfried Posch
Viruses 2025, 17(9), 1219; https://doi.org/10.3390/v17091219 - 7 Sep 2025
Viewed by 1795
Abstract
The COVID-19 pandemic has inflicted unprecedented pressure on communities and healthcare systems around the world. An outstandingly broad and intensive investigation of possible therapeutic interventions is currently taking place to prevent similar future threats to the global population. Investigating the related mechanisms of [...] Read more.
The COVID-19 pandemic has inflicted unprecedented pressure on communities and healthcare systems around the world. An outstandingly broad and intensive investigation of possible therapeutic interventions is currently taking place to prevent similar future threats to the global population. Investigating the related mechanisms of action is often complex and time consuming. Moreover, research on biochemical interactions of new drugs involves a considerable amount of effort, consequently bearing inherent financial and operational risks for pharmaceutical companies. An interesting approach to counteract colonization and infection is the concept of antiseptic treatment in vivo. Antiseptics are cost-effective and globally accessible, due to their ease of production, transportation and handling. A broad spectrum of active agents with different properties is readily available. One of these substances is hypochlorous acid (HOCl), which is also a naturally occurring biocidal agent and as such part of the innate immune system. Its successful history of medical use in wound treatment, combined with low cytotoxicity and documented efficacy against various pathogens, suggests that HOCl might be an effective agent for treating the respiratory mucosa. This could potentially enable therapeutic inhalation for combating bacterial infections and viral pathogens such as human respiratory syncytial, influenza, and SARS-CoV-2 viruses, which will be discussed in the present article. Full article
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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17 pages, 1575 KB  
Review
The Role of IL28B Polymorphism in Regulating Innate and Adaptive Immunity Against Viral Infection Among Allogenic Stem Cells Transplant Recipients
by Mohamed A. Eltokhy, Bhaumik Patel, Marina Curcic, Faizah Alabi, Shadan Modaresahmadi, Omar Eltoukhy, Esraa G. Abdelmageed and Sahar Radwan
Immuno 2025, 5(3), 38; https://doi.org/10.3390/immuno5030038 - 3 Sep 2025
Viewed by 675
Abstract
Viral infection is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), largely due to its impact on and interaction with immune reconstitution. Both innate and adaptive immunity are essential for effective viral control, yet their recovery post-transplant [...] Read more.
Viral infection is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), largely due to its impact on and interaction with immune reconstitution. Both innate and adaptive immunity are essential for effective viral control, yet their recovery post-transplant is often delayed or functionally impaired. Emerging evidence suggests genetic variation, particularly polymorphisms in the IL28B gene (encoding IFN-λ3), as a critical factor influencing the quality and timing of immune responses during the early post-transplant period. This review explores the role of IL28B polymorphisms in shaping antiviral immunity, in general, as well as after Allo-HSCT. IL28B variants have been implicated in modulating interferon-stimulated gene (ISG) expression, natural killer (NK) cell activity, and type I/III interferon signaling, all central components of innate immune defense against viral infections. Furthermore, IL28B polymorphisms, particularly rs12979860, have been shown in both general populations and limited HSCT cohorts to alter T cell response and interferon production, affecting reactivation and clearance of multiple viruses such as cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), COVID-19, and BK polyomavirus (BKPyV) as well as Graft vs. Host disease, thereby affecting adaptive immune reconstitution and long-term viral control. Understanding how IL28B genotype alters immune dynamics in transplant recipients could enhance risk stratification for CMV and other diseases and inform personalized prophylactic or therapeutic strategies. Therefore, this review highlights IL28B as a promising biomarker and potential immunoregulatory target in the management of viral infection post-Allo-HSCT. Full article
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11 pages, 813 KB  
Brief Report
Association Between Single-Nucleotide Polymorphism rs2287886 of CD209 Gene and Clinical Severity of COVID-19 in Unvaccinated Brazilian Patients
by Steffany Larissa Galdino Galisa, Raldney Ricardo Costa da Silva, Mell Cunha Aguiar, Marcus Villander Barros de Oliveira Sá, João Vinícius de Oliveira Melo, Giúlia Vitória Neves Pereira, José Rodolfo de Lima e Silva, Bianca de Lima Xavier Paiva, Andreza Gabriele da Silva Henrique, Rodrigo Feliciano do Carmo, Carlos Dornels Freire de Souza, Anderson da Costa Armstrong, Pablo Rafael Silveira Oliveira and Luydson Richardson Silva Vasconcelos
Genes 2025, 16(9), 1029; https://doi.org/10.3390/genes16091029 - 29 Aug 2025
Viewed by 599
Abstract
Background: Host genetic factors significantly influence individual susceptibility to severe COVID-19, potentially explaining the observed disparities in clinical outcomes across populations. One of the key effectors in innate immunity and antiviral defense is the CD209 gene. This study explored the potential correlation of [...] Read more.
Background: Host genetic factors significantly influence individual susceptibility to severe COVID-19, potentially explaining the observed disparities in clinical outcomes across populations. One of the key effectors in innate immunity and antiviral defense is the CD209 gene. This study explored the potential correlation of the CD209 gene SNP rs2287886 with diverse COVID-19 patient outcomes. Materials and Methods: A total of 176 patients (87 in the moderate group and 89 in the severe/critical/death group) were included in the study. Genotyping of patients was performed using the qPCR methodology, through the TAQMAN system. The results were analyzed adopting a significance level of p < 0.05. Results: The GG genotype (compared to AG + AA) and the G allele (compared to the A allele) of the rs2287886 SNP were significantly associated with an increased severity of COVID-19 (p = 0.0005 and p < 0.0001, respectively). The G allele was more frequent in individuals with more severe clinical outcomes (49.43% vs. 25.28%). Furthermore, expression quantitative trait loci (eQTL) analysis indicated that the GG genotype of rs2287886 is associated with higher CD209 gene expression. Furthermore, the observed interaction analysis suggests that the interactions between CD209 and its associated proteins may play a role in modulating the immune response. Conclusions: Our findings suggest that Brazilian patients homozygous for the GG genotype of the rs2287886 polymorphism in the CD209 gene may be at increased risk of severe COVID-19 in the Brazilian population and may act as a potential prognostic marker of disease severity. Full article
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16 pages, 698 KB  
Review
Broad-Spectrum Antiviral Activity of Cyclophilin Inhibitors Against Coronaviruses: A Systematic Review
by Abdelazeem Elhabyan, Muhammad Usman S. Khan, Aliaa Elhabyan, Rawan Abukhatwa, Hadia Uzair, Claudia Jimenez, Asmaa Elhabyan, Yee Lok Chan and Basma Shabana
Int. J. Mol. Sci. 2025, 26(16), 7900; https://doi.org/10.3390/ijms26167900 - 15 Aug 2025
Viewed by 777
Abstract
Cyclophilins (Cyps), a family of peptidyl-prolyl isomerases, play essential roles in the life cycle of coronaviruses by interacting with viral proteins and modulating host immune responses. In this systematic review, we examined cell culture, animal model, and clinical studies assessing the anti-viral efficacy [...] Read more.
Cyclophilins (Cyps), a family of peptidyl-prolyl isomerases, play essential roles in the life cycle of coronaviruses by interacting with viral proteins and modulating host immune responses. In this systematic review, we examined cell culture, animal model, and clinical studies assessing the anti-viral efficacy of cyclosporine A (CsA, PubChem CID: 5284373) and its non-immunosuppressive derivatives against coronaviruses. CsA demonstrated robust anti-viral activity in vitro across a broad range of coronaviruses, including but not limited to HCoV-229E, SARS-CoV, MERS-CoV, and SARS-CoV-2, with potent EC50 values in the low micromolar range. Non-immunosuppressive analogs such as Alisporivir and NIM811 exhibited similar inhibitory effects. In vivo, CsA treatment significantly reduced viral load, ameliorated lung pathology, and improved survival in coronavirus-infected animals. Clinical studies further indicated that CsA administration was associated with improved outcomes in COVID-19 patients, including reduced mortality and shorter hospital stays. Mechanistic studies revealed that CsA disrupts the formation of viral replication complexes, interferes with critical Cyp–viral protein interactions, and modulates innate immune signaling. These findings collectively demonstrate the therapeutic potential of cyclophilin inhibitors as broad-spectrum anti-virals against current and emerging coronaviruses. Full article
(This article belongs to the Section Molecular Immunology)
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25 pages, 3253 KB  
Review
Multisystem Endothelial Inflammation: A Key Driver of Adverse Events Following mRNA-Containing COVID-19 Vaccines
by János Szebeni and Akos Koller
Vaccines 2025, 13(8), 855; https://doi.org/10.3390/vaccines13080855 - 12 Aug 2025
Viewed by 3007
Abstract
mRNA-LNP-based COVID-19 vaccines, namely Pfizer-BioNTech’s Comirnaty and Moderna’s Spikevax, were successfully deployed to help control the SARS-CoV-2 pandemic, and their updated formulations continue to be recommended, albeit only for high-risk populations. One widely discussed aspect of these vaccines is their uniquely broad spectrum [...] Read more.
mRNA-LNP-based COVID-19 vaccines, namely Pfizer-BioNTech’s Comirnaty and Moderna’s Spikevax, were successfully deployed to help control the SARS-CoV-2 pandemic, and their updated formulations continue to be recommended, albeit only for high-risk populations. One widely discussed aspect of these vaccines is their uniquely broad spectrum and increased incidence of adverse events (AEs), collectively referred to as post-vaccination syndrome (PVS). Although the reported PVS rate is low, the high number of administered doses among healthy individuals has resulted in a substantial number of reported vaccine-related injuries. A prominent manifestation of PVS is multisystem inflammation, hypothesized to result from the systemic transfection of organ cells with genetic instructions for a toxin, the spike protein, delivered with lipid nanoparticles (LNPs). In this narrative review, we focus on endothelial cells in the microcirculatory networks of various organs as primary sites of transfection with mRNA-LNP and consequent PVS. We outline the anatomical variations in the microcirculation contributing to the individual variability of symptoms and examine the molecular and cellular responses to vaccine nanoparticle exposure at the endothelial cell level with a focus on the pathways of a sustained cascade of toxic and autoimmune processes. A deeper understanding of the mechanisms underlying mRNA-LNP-induced AEs and PVS at the organ and cellular levels is critical for improving the safety of future vaccines and other therapeutic applications of this groundbreaking technology. Full article
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16 pages, 875 KB  
Article
Profile of Selected MicroRNAs as Markers of Sex-Specific Anti-S/RBD Response to COVID-19 mRNA Vaccine in Health Care Workers
by Simona Anticoli, Maria Dorrucci, Elisabetta Iessi, Salvatore Zaffina, Rita Carsetti, Nicoletta Vonesch, Paola Tomao and Anna Ruggieri
Int. J. Mol. Sci. 2025, 26(15), 7636; https://doi.org/10.3390/ijms26157636 - 7 Aug 2025
Viewed by 932
Abstract
Sex-based immunological differences significantly influence the outcome of vaccination, yet the molecular mediators underpinning these differences remain largely elusive. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have emerged as critical modulators of innate and adaptive immune responses. In this study, we investigated [...] Read more.
Sex-based immunological differences significantly influence the outcome of vaccination, yet the molecular mediators underpinning these differences remain largely elusive. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have emerged as critical modulators of innate and adaptive immune responses. In this study, we investigated the expression profile of selected circulating miRNAs as potential biomarkers of sex-specific humoral responses to the mRNA COVID-19 vaccine in a cohort of health care workers. Plasma samples were collected longitudinally at a defined time point (average 71 days) post-vaccination and analyzed using RT-qPCR to quantify a panel of immune-relevant miRNAs. Anti-spike (anti-S) IgG titers were measured by chemiluminescent immunoassays. Our results revealed sex-dependent differences in miRNA expression dynamics, with miR-221-3p and miR-148a-3p significantly overexpressed in vaccinated female HCWs and miR-155-5p overexpressed in vaccinated males. MiR-148a-3p showed a significant association with anti-S/RBD (RBD: receptor binding domain) IgG levels in a sex-specific manner. Bioinformatic analysis for miRNA targets indicated distinct regulatory networks and pathways involved in innate and adaptive immune responses, potentially underlying the differential immune activation observed between males and females. These findings support the utility of circulating miRNAs as minimally invasive biomarkers for monitoring and predicting sex-specific vaccine-induced immune responses and provide mechanistic insights that may inform tailored vaccination strategies. Full article
(This article belongs to the Special Issue Molecular Research on Immune Response to Virus Infection and Vaccines)
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24 pages, 3590 KB  
Article
Mesocricetus auratus (Golden Syrian Hamster) Experimental Model of SARS-CoV-2 Infection Reveals That Lung Injury Is Associated with Phenotypic Differences Between SARS-CoV-2 Variants
by Daniela del Rosario Flores Rodrigues, Alexandre dos Santos da Silva, Arthur Daniel Rocha Alves, Bárbara Araujo Rossi, Richard de Almeida Lima, Sarah Beatriz Salvador Castro Faria, Oswaldo Gonçalves Cruz, Rodrigo Muller, Julio Scharfstein, Amanda Roberta Revoredo Vicentino, Aline da Rocha Matos, João Paulo Rodrigues dos Santos, Pedro Paulo Abreu Manso, Milla Bezerra Paiva, Debora Ferreira Barreto-Vieira, Gabriela Cardoso Caldas, Marcelo Pelajo Machado and Marcelo Alves Pinto
Viruses 2025, 17(8), 1048; https://doi.org/10.3390/v17081048 - 28 Jul 2025
Viewed by 1179
Abstract
Despite the current level of public immunity to SARS-CoV-2, the early inflammatory events associated with respiratory distress in COVID-19 patients are not fully elucidated. Syrian golden hamsters, facultative hibernators, recapitulate the phenotype of SARS-CoV-2-induced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—induced severe acute [...] Read more.
Despite the current level of public immunity to SARS-CoV-2, the early inflammatory events associated with respiratory distress in COVID-19 patients are not fully elucidated. Syrian golden hamsters, facultative hibernators, recapitulate the phenotype of SARS-CoV-2-induced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—induced severe acute lung injury seen in patients. In this study, we describe the predominance of the innate immune response in hamsters inoculated with four different SARS-CoV-2 variants, underscoring phenotypic differences among them. Severe inflammatory lung injury was chronologically associated with acute and significant weight loss, mainly in animals inoculated with A.2 and Delta variants. Omicron-infected animals had lower overall histopathology scores compared to other variants. We highlight the central role of endothelial injury and activation in the pathogenesis of experimental SARS-CoV-2 infection in hamsters, characterised by the presence of proliferative type I and type II pneumocytes with abundant surfactant expression, thereby maintaining hyperinflated alveolar fields. Additionally, there was evidence of intrapulmonary lymphatic vessel proliferation, which was accompanied by a lack of detectable microthrombosis in the lung parenchyma. However, white microthrombi were observed in lymphatic vessels. Our findings suggest that the physiological compensatory mechanisms that maintain respiratory homeostasis in Golden Syrian hamsters prevent severe respiratory distress and death after SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Emerging Concepts in SARS-CoV-2 Biology and Pathology, 3rd Edition)
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11 pages, 479 KB  
Article
Association of TMEM173/STING1 Gene Variants with Severe COVID-19 Among Fully Vaccinated vs. Non-Vaccinated Individuals
by Daniel Vázquez-Coto, Marta García-Clemente, Guillermo M. Albaiceta, Laura Amado, Lorena M. Vega-Prado, Claudia García-Lago, Rebeca Lorca, Juan Gómez and Eliecer Coto
Life 2025, 15(8), 1171; https://doi.org/10.3390/life15081171 - 23 Jul 2025
Viewed by 727
Abstract
Background. The STING protein is activated by the second messenger cGAMP to promote the innate immune response against infections. Beyond this role, a chronically overactive STING signaling has been described in several disorders. Patients with severe COVID-19 exhibit a hyper-inflammatory response (the cytokine [...] Read more.
Background. The STING protein is activated by the second messenger cGAMP to promote the innate immune response against infections. Beyond this role, a chronically overactive STING signaling has been described in several disorders. Patients with severe COVID-19 exhibit a hyper-inflammatory response (the cytokine storm) that is in part mediated by the cGAS-STING pathway. Several STING inhibitors may protect from severe COVID-19 by down-regulating several inflammatory cytokines. This pathway has been implicated in the establishment of an optimal antiviral vaccine response. STING agonists as adjuvants improved the IgG titers against the SARS-CoV-2 Spike protein vaccines. Methods. We investigated the association between two common functional STING1/TMEM173 polymorphisms (rs78233829 C>G/p.Gly230Ala and rs1131769C>T/p.His232Arg) and severe COVID-19 requiring hospitalization. A total of 801 non-vaccinated and 105 fully vaccinated (mRNA vaccine) patients, as well as 300 population controls, were genotyped. Frequencies between the groups were statistically compared. Results. There were no differences for the STING1 variant frequencies between non-vaccinated patients and controls. Vaccinated patients showed a significantly higher frequency of rs78233829 C (230Gly) compared to non-vaccinated patients (CC vs. CG + GG; p = 0.003; OR = 2.13; 1.29–3.50). The two STING1 variants were in strong linkage disequilibrium, with the rs78233829 C haplotypes being significantly more common in the vaccinated (p = 0.02; OR = 1.66; 95%CI = 1.01–2.55). We also studied the LTZFL1 rs67959919 G/A polymorphism that was significantly associated with severe COVID-19 (p < 0.001; OR = 1.83; 95%CI = 1.28–2.63). However, there were no differences between the non-vaccinated and vaccinated patients for this polymorphism. Conclusions. We report a significant association between common functional STING1 polymorphisms and the risk of developing severe COVID-19 among fully vaccinated patients. Full article
(This article belongs to the Section Genetics and Genomics)
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17 pages, 3305 KB  
Article
Evolution of Blood Innate Immune Cell Phenotypes Following SARS-CoV-2 Infection in Hospitalized Patients with COVID-19
by Arnaud Dendooven, Stephane Esnault, Marie Jacob, Jacques Trauet, Emeline Delaunay, Thomas Guerrier, Amali E. Samarasinghe, Floriane Mirgot, Fanny Vuotto, Karine Faure, Julien Poissy, Marc Lambert, Myriam Labalette, Guillaume Lefèvre and Julie Demaret
Cells 2025, 14(14), 1093; https://doi.org/10.3390/cells14141093 - 17 Jul 2025
Cited by 1 | Viewed by 913
Abstract
Innate immune cells appear to have an important implication in the resolution and/or the aggravation of the COVID-19 pathogenesis after infection with SARS-CoV-2. To better appreciate the role of these cells during COVID-19, changes in blood eosinophil, the neutrophil and monocyte count, and [...] Read more.
Innate immune cells appear to have an important implication in the resolution and/or the aggravation of the COVID-19 pathogenesis after infection with SARS-CoV-2. To better appreciate the role of these cells during COVID-19, changes in blood eosinophil, the neutrophil and monocyte count, and levels of surface protein markers have been reported. However, analyses at several timepoints of multiple surface markers on granulocytes and monocytes over a period of one month after a SARS-CoV-2 infection are missing. Therefore, in this study, we performed blood eosinophil, neutrophil, and monocyte phenotyping using a list of surface proteins and flow cytometry during a period of 30 days after the hospitalization of patients with severe SARS-CoV-2 infections. Blood cell counts were reported at seven different timepoints over the 30-day period as well as measures of multiple mediators in serum using a targeted multiplex assay approach. Our results indicate a 95% drop in the blood eosinophil count by D1, with eosinophils displaying a phenotype defined as CD69/CD63/CD125high and CCR3/CD44low during the early phases of hospitalization. Conversely, by D7 the neutrophil count increased significantly and displayed an immature, activated, and immunosuppressive phenotype (i.e., 3% of CD10/CD16low and CD10lowCD177high, 6.7% of CD11bhighCD62Llow, and 1.6% of CD16highCD62Llow), corroborated by enhanced serum proteins that are markers of neutrophil activation. Finally, our results suggest a rapid recruitment of non-classical monocytes leaving CD163/CD64high and CD32low monocytes in circulation during the very early phase. In conclusion, our study reveals potential very early roles for eosinophils and monocytes in the pathogenesis of COVID-19 with a likely reprogramming of eosinophils in the bone marrow. The exact roles of the pro-inflammatory neutrophils and the functions of the eosinophils and the monocytes, as well as these innate immune cell types, interplays need to be further investigated. Full article
(This article belongs to the Special Issue Eosinophils and Their Role in Allergy and Related Diseases)
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