#Autoantibodies against type I #interferons in patients with #zoonotic #H7N9 #influenza: an observational case–control study

 

Summary

Background

The determinants of the species barrier preventing human infections with avian influenza A viruses (IAV) are incompletely understood. We previously identified loss-of-function variants of the interferon-regulated antiviral factor MxA as a genetic factor for increased susceptibility to infections with the H7N9 subtype. Given the central role of type I IFNs (IFN-I) in antiviral defence, we hypothesised that IFN-I-neutralising autoantibodies may similarly predispose to zoonotic H7N9 infection.

Methods

In this observational case–control study, serum samples collected between 2013 and 2017 from 199 Chinese patients with laboratory-confirmed H7N9 infection and 531 healthy, uninfected controls (269 poultry workers, 262 close contacts) were screened for IgG autoantibodies binding IFNα2, IFNβ1b, or IFNω using a multiplex bead-based assay. Positive samples were tested for IFN-neutralising activity in a luciferase-based reporter assay. To confirm their ability to block IFNα2-mediated antiviral activity, selected samples (n = 19) were analysed in IAV infection experiments. Associations between age, sex, H7N9 case status, case fatality, and the presence of neutralising autoantibodies were evaluated by logistic regression. Available whole-genome sequencing data from 26 individuals with neutralising autoantibodies were screened for variants in genes linked to IFN-I autoimmunity.

Findings

Neutralising autoantibodies against at least one IFN-I were detected in 19.1% (38/199) of patients but in only 1.1% (6/531) of controls, consistent with published general population data. Most patient sera targeted IFNα2 and/or IFNω (35/199), and 18.1% (36/199) neutralised even high IFN-I concentrations of 1–10 ng/ml. The presence of neutralising autoantibodies was associated with 8.2- to 25.3-fold higher odds of H7N9 infection (p < 0.0001), depending on antibody specificity and reference group. Autoantibody prevalence increased significantly with age in patients (44.8% ≥70 years; OR = 1.05; 95% CI 1.02–1.07; p = 0.0001), but was not associated with sex (OR for males vs. females = 0.52; 95% CI 0.23–1.14; p = 0.106). All selected sera containing neutralising autoantibodies blocked IFNα2-induced antiviral activity in cell culture. No known genetic predisposition for IFN-I autoimmunity was identified.

Interpretation

Our findings suggest that IFN-I-targeting autoimmunity is associated with susceptibility to zoonotic IAV infection with the H7N9 subtype, and possibly also other subtypes, including panzootic H5N1. Given the ease of implementation, screening for anti-IFN-I autoantibodies could be readily integrated into surveillance or targeted testing. This could be relevant in environments with increased exposure to zoonotic IAVs.

Funding

Shenzhen Medical Research Fund, National Natural Science Foundation of China, Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences, Guangdong Provincial Science and Technology Program, Program for Youzuzhikeyan of Shenzhen University, German Research Foundation, Swiss National Science Foundation.

Source: 

Link: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(26)00271-9/fulltext

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The #NK Cell #Landscape in the Natural History of #Hantavirus Cardiopulmonary Syndrome in a Chilean Cohort

 

Abstract

Hantavirus cardiopulmonary syndrome (HCPS) caused by Andes Orthohantavirus (ANDV) carries case-fatality rates up to 40%; however, the innate immune determinants of disease severity remain poorly defined. Natural killer (NK) cells are central mediators of early antiviral immunity, but their landscape during the earliest phase of ANDV infection has not been characterized. Using multiparameter flow cytometry and unsupervised UMAP-based clustering in PBMCs from 13 HCPS patients stratified by severity and nine healthy donors, we show that severe HCPS is characterized by a coordinated disruption of the CD56dim NK cell compartment, encompassing reduced subset frequencies, specific reduction in the terminally differentiated NKG2C+CD57+ adaptive-like pool, and intrinsic impairment of IFN-γ production and degranulation, deficits that were absent in mild patients and persisted in part beyond clinical recovery. Furthermore, CD56dimCD16+ NK cell frequencies correlated negatively with viral load across all acute patients, independent of clinical severity. These findings establish severe HCPS not merely as a state of NK cell depletion, but as one of selective functional impairment of the most cytotoxically competent NK cell population during the critical early acute phase of ANDV infection.

Source: 

Link: https://www.mdpi.com/1999-4915/18/7/712

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Systemic #atopy and upper - #airway disease define susceptibility to incident #asthma after #COVID19 in #Korea

 

Abstract

Incident asthma is an important respiratory sequela after COVID-19, but it is unclear which allergic phenotypes amplify risk. Using a linked nationwide Korean database of 3,987,182 individuals with confirmed severe acute respiratory syndrome coronavirus 2 infection, we compare claims-based incident asthma in those with pre-existing systemic atopy and/or upper-airway disease (allergic rhinitis, chronic rhinosinusitis, atopic dermatitis or food allergy) versus those without after 1:1 propensity score matching. During follow-up to 31 December 2022, participants with pre-existing disease have higher asthma incidence than matched controls (3.55 vs 2.13 per 1,000 person-years), with a hazard ratio of 1.66 (95% confidence interval 1.58–1.75). Asthma risk is elevated for each condition and increases with greater disease burden. These findings show that pre-existing allergic and upper-airway phenotypes stratify post-COVID incident asthma risk on a national scale, supporting targeted surveillance in high-risk subgroups.

Source: 

Link: https://www.nature.com/articles/s41467-026-74860-w

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TAG-TP #statement on #immunomodulators and host-directed #therapies for #Bundibugyo virus disease (WHO, June 26 '26)

    In the context of prioritization of therapeutics to be included in clinical research for Bundibugyo virus disease (BVD) the Technical Advisory Group on Therapeutics Prioritization (TAG-TP) has begun examining the landscape of immunomodulatory and host-directed new or repurposed agents. 

    Currently, there are no studies in patients characterizing the downstream pathogenesis that follows infection with Bundibugyo virus (BDBV). 

    The available evidence derives mainly from data collected with Ebola virus, specifically Zaire ebolavirus (EBOV) that provides relevant information from animal models and patients, but not sufficient to allow a proper assessment for the selection of immunomodulatory and host-directed candidates for clinical trials in BVD. 

    In addition, it is noted that even corticosteroids have never been tested in a stringent filovirus animal model. 

    For other infectious diseases leading to sepsis or other severe disease evolutions, it is also noted that immunomodulators can be beneficial or detrimental depending on the timing of the administration.

    To allow for a proper scientific evaluation of the different potential interventions, the appropriate timing of administration and the appropriate patient selection for inclusion in large clinical trials, it is imperative to generate quality data on the natural history of BVD from people infected with BDBV. 

    This would likely need to occur at select clinical sites that are adequately equipped to collect and analyze samples from patients with BVD. 

    Suggested data for collection include immune makers associated with inflammation and innate/adaptive immunity, correlative viral load and clinical features, markers of coagulation perturbation and organ/tissue damage. 

    This will help identify biomarkers pertaining to a pro-inflammatory status with co-relation to clinical phenotypes and organ dysfunction.

    Only in this way will it be possible to identify and/or confirm potential pharmacological targets and related potential interventions. 

    Collecting further evidence is paramount to minimizing risks to participants in clinical trials, as, depending on individual patient phenotypes and the status of disease evolution, the administration of some immunomodulatory agents may result in detrimental effects (e.g. on viral replication).

    In addition, some of these clinical investigations may have to be tailored to specific immune phenotypes based on the pharmacological activity of the investigational candidate, but sophisticated biomarker testing should be avoided to ensure implementation of clinical trials at BDBV Treatment Units.

    Lastly, timely availability of data from animal models would also provide evidence to facilitate the identification of the most promising therapies for inclusion in clinical trials.

Source: 

Link: https://www.who.int/news/item/26-06-2026-tag-tp-statement-on-immunomodulators-and-host-directed-therapies-for-bundibugyo-virus-disease

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#Antibodies against #influenza #H1N1pdm2009 and B/Victoria strains but not #H3N2 are increased in recent onset type 1 #narcolepsy versus matched controls

 

Abstract

Study Objectives: 

Onsets of Narcolepsy type-1 (NT1) increased following A/H1N1 vaccination with PandemrixTM in Europe and with A/H1N1pdm2009 infections in China and other countries. To test if other strains could trigger narcolepsy, we measured strain-specific antibodies in patients with recent onset NT1 compared to controls. 

Methods: 

Antibodies against hemagglutinin (HA) and neuraminidase (NA) were tested in 62 patients with very recent onset (onset and blood collection following a single flu season, mean +/- SEM: 0.44 +/- 0.06 years since onset) and 100 controls matched by age, sex, season and year of collection (2000-2025). Results were next extended to 181 recent onset patients (mean +/- SEM: 1.00 +/- 0.05 years) versus 260 controls, matched by sex, season and year, but having a slightly higher mean age. HA inhibition (HAI) and NA inhibition (NAI) assays were conducted using flu strains known to circulate during the corresponding flu seasons. HAI results are shown as % positive (titers >= 40) and NAI results as geometric mean titers. Odds ratio (OR) and coefficient were used to compare antibody titers in NT1 versus controls. The contribution of each assay to prediction was finally quantified in the larger sample set using Shapley decomposition. 

Results: 

NT1 patients had increased anti-HA and anti-NA antibodies against A/H1N1pdm2009 (anti-HA OR = 3.86, anti-NA coefficient = 0.35) and B/Victoria (anti-HA OR =1.90, anti-NA coefficient = 0.22), but not A/H1N1pre2009, A/H3N2, or B/Yamagata, independent of HLA-DQB1*06:02 status, age, sex, and flu season. Correlations between anti-HA and anti-NA antibodies titers were weak to moderate but significant (r2=-0.10 to 0.34). Multivariable model outperformed age-only baseline (McFadden R2 = 0.19 vs. 0.03; AUC = 0.79 vs. 0.64; likelihood-ratio test X2 = 51, p<0.001), with anti-HA against A/H1N1pdm2009 (coefficient = 0.78, p < 0.001) and anti-NA against B/Victoria (coefficient = 0.69, p < 0.001) emerging as the strongest independent predictors. 

Conclusions: 

A/H1N1pdm2009 and B/Victoria, but not other strains can trigger the autoimmune process leading to orexin cell loss in narcolepsy.

Competing Interest Statement

The authors have declared no competing interest.

Source: 

Link: https://www.medrxiv.org/content/10.64898/2026.06.13.26355596v1

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Could #bradykinin #pathway inhibition change the course of severe #hantavirus disease?

 

Highlights

    • Hantavirus triggers the kallikrein–kinin system, driving severe capillary leak.

    • In vitro data show that bradykinin directly disrupts endothelial barrier function.

    • Two clinical cases support targeting the bradykinin pathway with icatibant.

Abstract

A recent multi-country hantavirus outbreak associated with a cruise ship underscores the urgent need to understand the mechanisms driving severe vascular leakage and multi-organ failure. While disease severity is largely attributed to a dysregulated host immune response and intense cytokine surge, the precise molecular mediators remain incompletely defined. Laboratory evidence indicates that hantavirus infection activates the factor XII–dependent kallikrein–kinin system, leading to elevated bradykinin production and subsequent endothelial barrier dysfunction. This translational mechanism is tentatively supported by two clinical case reports where severe hantavirus infections were successfully treated with the bradykinin receptor antagonist icatibant. We hypothesize that exaggerated bradykinin signalling drives the vascular leak phenotype, making the kallikrein–kinin pathway a compelling therapeutic target. Ultimately, effectively combating hantavirus-induced vascular permeability may require a multi-faceted approach combining targeted bradykinin inhibition with broader immunomodulatory strategies.

Source: 

Link: https://www.sciencedirect.com/science/article/abs/pii/S016524782600074X?via%3Dihub

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A single PA-X #mutation in #bovine-origin #H5N1 #influenza virus reduces #pathogenicity in mice

 

Abstract

Dairy cows have emerged as a reservoir for human infection with highly pathogenic avian influenza (HPAI) H5N1. At the bovine-human interface, H5N1 strains may acquire adaptive mutations that influence their zoonotic potential. Sequence analysis identified a K142E substitution (bovine to human) in the PA and PA-X proteins, with the potential to affect both polymerase activity and host shutoff. Here, we used a loss-of-function approach to investigate how the bovine substitution (E142K) in PA/PA-X impacts viral replication, host shutoff activity, and pathogenicity in the human H5N1 background. Viral growth kinetics demonstrated that the virus containing the E142K substitution is attenuated, with reduced replication compared to wild-type (WT) virus. Consistently, PA-X-mediated host shutoff activity was reduced, resulting in increased induction of interferon (IFN) responses relative to WT. In vivo, mice infected with the E142K mutant virus survived, whereas infection with the WT virus was uniformly lethal. Despite comparable viral titers and inflammation score in mouse lungs, cytokine and chemokine profiling revealed distinct immune responses, with reduced CCL2 and increased CCL5 and IFN-γ in mice infected with the E142K mutant virus compared to mice infected with the WT virus. These findings indicate that increased virulence of the human-adapted strain is driven by a PA-X mutation that modulates inflammatory responses, producing distinct immune signatures linked to host survival or viral lethality rather than changes in polymerase activity by PA. Collectively, these results highlight PA-X as a key determinant of pathogenicity of H5N1 and a potential target for the rational design of antiviral strategies.

Competing Interest Statement

The authors have declared no competing interest.

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.05.09.724031v1

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#Replication Efficiency of Contemporary Highly Pathogenic Avian #Influenza #H5N1 Virus Isolates in #Human #Nasal Epithelium Model

 

Abstract

Replication of influenza A virus in human nasal epithelium affects transmissibility and disease. We compared virus replication and immune responses in human nasal epithelium infected with seasonal and highly pathogenic avian influenza A(H5N1) viruses. Contemporary H5N1 viruses replicated better than the historical isolate; however, interferon response to B3.13 genotype viruses was dampened.

Source: 

Link: https://wwwnc.cdc.gov/eid/article/32/5/26-0053_article

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High #risk of hypoxemic #COVID19 #pneumonia in #myasthenia gravis patients with type I IFN #autoantibodies

 

Abstract

Patients with myasthenia gravis (MG) may produce autoantibodies neutralizing type I interferons (AAN-I-IFN), which have been shown to underlie severe viral diseases, including critical COVID-19 pneumonia, in patients without MG. We studied an international cohort of 85 unvaccinated SARS-CoV-2-infected MG patients with no antiviral treatment. Hypoxemic pneumonia occurred in 48 of these patients, including 22 (45.8%) with AAN-I-IFN, which neutralized both IFN-α2 and IFN-ω in 14 (29.2%) patients. Six (16.2%) of the remaining 37 patients had AAN-I-IFN, which neutralized both IFN-α2 and IFN-ω in three patients. The risk of hypoxemic pneumonia was greater in MG patients with AAN-I-IFN neutralizing 10 ng/mL of both IFN-α2 and IFN-ω (odds ratio and 95% confidence interval (OR [95% CI]): 12.7 [2.1-78.9], p=0. 0010) or IFN-α2 at any dose (4.7 [1.5-15.0], p=0.0054) than in those without such autoantibodies. The risk of AAN-I-IFN production was much higher in MG patients than in the general population (28.9 [10.8-77.7], p=4.9x10-27). Fourteen patients had thymoma, which increased the risk of AAN-I-IFN (64% versus 27%, (OR [95% CI]: 5.6 [1.6-19.4], p=0.0050) and hypoxemic pneumonia (9.2 [1.9-44.2]; p=0.0019). Thymoma is, thus, associated with a higher risk of producing AAN-I-IFN, and these autoantibodies are associated with a higher risk of developing life-threatening COVID-19 pneumonia in patients with MG.

Competing Interest Statement

J.-L. C. is an inventor on patent application PCT/US2021/042741, filed July 22, 2021, submitted by The Rockefeller University and covering the diagnosis of susceptibility to, and the treatment of, viral disease, and viral vaccines, including COVID-19 and vaccine-associated diseases. None of the other authors has any conflict of interest to declare.

Funding Statement

The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI163029), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the Fisher Center for Alzheimer s Research Foundation, the Meyer Foundation, the JPB Foundation, the Stavros Niarchos Foundation (SNF) as part of its grant to the SNF Institute for Global Infectious Disease Research at The Rockefeller University, the French Agence Nationale de la Recherche (ANR) under the France 2030 program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU202503020018), the ANR-RHU program ANR-21-RHUS-0008, ANR GENVIR (ANR-20-CE93-0003), ANR AABIFNCOV (ANR-20-CO11-0001) and ANR GenMISC (ANR-21-COVR-0039), AI2D (ANR-22-CE15-0046) projects, the European Union s Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 101057100 (UNDINE), the Square Foundation, Grandir - Fonds de solidarite pour l enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea and Bowery Advisory Group; The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), William E. Ford, General Atlantic s Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic s Co-President, Managing Director and Head of Business in EMEA, and the General Atlantic Foundation, Institut National de la Sante et de la Recherche Medicale (INSERM), REACTing-INSERM and Paris Cite University. For the collection and biobanking of MG samples, RLP and FT acknowledge support provided by the FP6 program (MYASTAID, LSHM-CT-2006-037833), FIGHT-MG (HEALTH-2009-242-210). N.L. was supported by the Swedish Research Council (no 2021-03118) and the Goran Gustafsson Foundation (no 2141 and 2247). TLV was supported by a Poste CCA-INSERM-Bettencourt (with the support of the Fondation Bettencourt-Schueller). P.B. was supported by the French Foundation for Medical Research (FRM, EA20170638020), the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller), and a Poste CCA-INSERM-Bettencourt (with the support of the Fondation Bettencourt-Schueller).

Source: 

Link: https://www.medrxiv.org/content/10.64898/2026.03.27.26349525v1

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Intravenous #immunoglobulin #treatment for #longCOVID: a case report of clinical and immunological findings

 

Summary

A previously healthy 39-year-old man developed highly symptomatic post-COVID-19 condition (also known as long COVID) marked by cognitive dysfunction, disabling fatigue, and autonomic symptoms unresponsive to multiple multidisciplinary interventions. Given the presence of markedly elevated serum autoantibodies against G protein-coupled receptors, high-dose intravenous immunoglobulin therapy was initiated at 400 mg/kg per day for 5 consecutive days. After 4 weeks, a maintenance dose of 500 mg/kg was administered for 1 day, followed by two further maintenance cycles consisting of 500 mg/kg per day for 3 consecutive days, each given at 4-week intervals. In parallel, the patient underwent a cognitive stimulation intervention. Neurological symptoms were assessed with the Fatigue Assessment Scale and the WHO Disability Assessment Schedule 2.0, and the immunological profile was longitudinally analysed during intravenous immunoglobulin treatment. Fatigue scores normalised, neurocognitive performance returned to normal value, and quality of life improved after the first infusion and fully recovered within 1 year. Immunological profiling revealed the presence of an inverted CD4 to CD8 T-cell ratio that persisted during the whole follow-up. We also identified a CD8+ T cell–monocyte complex and spontaneous IFNγ release. Intravenous immunoglobulin therapy was associated with a significant reduction of these complexes, spontaneous IFNγ and TNF production, markers of endothelial inflammation, and circulating autoantibody titres. This patient provides exploratory evidence that high-dose intravenous immunoglobulin was associated with sustained clinical recovery from long COVID over 1 year of follow-up, accompanied by immunological changes consistent with modulation of post-viral immune dysregulation, including a reduction in pathogenic T cell–monocyte synapses. Although causal inference cannot be established from a single patient, these findings suggest that this cellular interaction can contribute to long COVID and that immunomodulation could represent a rational therapeutic approach to be evaluated in selected patients.

Source: 

Link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(26)00063-0/abstract?rss=yes

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Defining #influenza-specific B cells in #vaccine #responders, non-responders and influenza breakthrough #infections

 

Abstract

Although seasonal influenza vaccination programs are effective at a population level, our data from inactivated influenza vaccine (IIV) cohorts in years 2015-2022 reveal that 50-60% of individuals do not seroconvert following immunization. The underlying mechanisms of vaccine non-responsiveness are far from understood. In this study, we sought to define key determinants of optimal B cell immune responses elicited by seasonal influenza vaccination, and to explore why some individuals fail to elicit humoral immunity following immunization. Immune responses associated with seroconversion and vaccine failure from individuals immunized with IIVs were compared at cellular and molecular levels using single-cell transcriptomics. We analyzed HA-specific B cell immunity across vaccine-responders, breakthrough infections and patients hospitalized with acute influenza. Droplet-based single-cell RNA sequencing and VDJ-sequencing of influenza-specific B cells from stored PBMCs was performed using 10x Genomics. Our results show that atypical B cells are the major subset of B cell responses in vaccine non-responders on day 28 post-vaccination. Conversely, individuals who seroconvert had diverse B cell phenotypes. The use of recombinant influenza-specific HA probes allowed us to dissect expression patterns on influenza HA-specific B cells. We found that HA-specific B cells of vaccine non-responders for A/H1N1 and A/H3N2 components displayed elevated atypical-like markers (CD11c, FcRL-5) at baseline, compared to responders. Analysis of differentially expressed genes (DEGs) between responders and non-responders identified differential expression of HLA-DR, CD74, CD83, and CXCR3 genes. We subsequently demonstrated reduced frequencies of HLA-DR-, CD74- and CD83-expressing B cells in patients hospitalized with influenza, compared to healthy participants. Hospitalized influenza patients also had significantly higher proportions of atypical CD21-CD27- B cells. Overall, our data demonstrate an association between elevated frequencies of atypical-like B cells with both lack of seroconversion following immunization and severe influenza infection. These findings broaden our understanding of humoral immunity in influenza vaccination and infection, providing novel insights for vaccination strategies and design.

Competing Interest Statement

Katherine Kedzierska has received paid honoraria from Pfizer. Hayley McQuilten has a consultancy role for Ena Therapeutics

Funder Information Declared

NHMRC

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.03.19.710321v1

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Empiric #azithromycin alters the upper respiratory #microbiome and #resistome without anti-inflammatory benefit in #COVID19

 

Abstract

Azithromycin is a widely used antibiotic and was frequently used to treat hospitalized patients during the COVID-19 pandemic. The impact of empiric azithromycin use on the respiratory microbiome in patients with viral respiratory infections is unclear. Here we used longitudinal metatranscriptomics on nasal swabs from a prospective multicentre cohort of 1,164 patients hospitalized for COVID-19. We compared the upper respiratory microbiome, resistome and systemic immune response in patients treated with azithromycin (n = 366) with those who received no antibiotics (n = 474) or other antibiotics (n = 324). We found that azithromycin altered microbiome composition and increased the expression and relative proportion of macrolide/lincosamide/streptogramin (MLS) resistance genes. These changes occurred after 1 day of exposure and persisted for over a week. MLS resistance gene expression was associated with commensals and potential pathogens, while there were no differences in host inflammatory gene expression in blood and airways. This demonstrates that empiric azithromycin treatment impacts the upper respiratory microbiome and resistome without apparent anti-inflammatory benefit.

Source: 

Link: https://www.nature.com/articles/s41564-026-02285-8

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PA-X 122V broadly determines the #host shutoff #activity of #influenza A viruses

 

ABSTRACT

Multiple genes are involved in the pathogenicity of influenza A virus. Our previous study reported two naturally occurring amino acid mutations in the polymerase acidic (PA) protein as crucial determinants of the virulence of Eurasian avian-like H1N1 (EA H1N1) influenza viruses. PA-X, an accessory protein encoded by the PA gene, is thought to play a role in viral pathogenicity and regulation of host immune response, but its specific function remains unclear. In this study, we found that two genetically similar EA H1N1 influenza viruses, A/swine/Liaoning/FX38/2017 (FX38) and A/swine/Liaoning/SY72/2018 (SY72), induced significantly different suppression levels of host protein synthesis. The difference in host shutoff activity induced by PA-X protein was the key factor affecting the inhibition of host gene expression. Loss of PA-X expression significantly reduced its host shutoff activity, thereby enhancing host antiviral immune response. PA-X deficiency had no apparent effect on polymerase activity or replication capacity. We pinpointed a single residue 122V involved in the ability of PA-X to inhibit host gene expression and thereby modulate the host antiviral response. Notably, PA-X 122V was highly conserved among multiple subtypes of influenza A viruses and vital for maintaining the inhibitory effects on the host protein synthesis. Together, these findings demonstrate that the PA-X protein plays a major role in the suppression of host protein synthesis during influenza virus infection and elucidate the molecular mechanism by which the amino acid residue 122V in PA-X facilitates its suppression effects on host innate immune responses.

Source: 

Link: https://journals.asm.org/doi/full/10.1128/mbio.03433-25?af=R

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Resistance of #endothelial cells to #SARS-CoV-2 #infection in vitro

 

ABSTRACT

The secondary thrombotic/vascular clinical syndrome of COVID-19 suggests that SARS-CoV-2 infects the endothelium; however, robust in vitro infection of endothelial cells by various strains of SARS-CoV-2 remains to be demonstrated and continues to be debated. Here, we revisit the question of endothelial cell permissiveness to SARS-CoV-2 using isolated endothelial cells (from the lung, aorta, and endothelial cell progenitors), and additionally, to overcome limitations associated with cultured cells, using native endothelial cells within living precision cut human lung slices and single-cell RNA sequencing to track viral presence. Cellular infection in endothelial monocultures was determined using fluorescence imaging. Mediator release was measured by ELISA, and gene expression was assessed by RT-qPCR. Infection in lung slices was determined using single-cell RNA sequencing, capturing molecular identifiers that aligned to the SARS-CoV-2 viral genome (for lung slices). Each cultured endothelial cell type displayed functional viral responses by increased release of IP-10 when stimulated with Poly-IC (TLR3) or Imiquimod (TLR7/8). Compared to nasal epithelial cells, endothelial cells expressed low or undetectable levels of ACE2 and showed susceptibility to Ebola and Vesicular Stomatitis Virus glycoprotein-expressing pseudoviruses but not live SARS-CoV-2. Importantly, native endothelial cells within human lung slices displayed minimal infectability with SARS-CoV-2. To our knowledge, this is the first study to demonstrate that neither cultured nor native human endothelial cells are particularly, directly permissive to SARS-CoV-2, likely due to the lack of sufficient AEC2 expression. These observations confirm that the vascular inflammation and cardiovascular consequences of COVID-19 are largely an indirect result of paracrine inflammatory responses.

IMPORTANCE

SARS-CoV-2 is recognized not only for its acute effects and links with cardiovascular events but also for its ability to cause long COVID syndrome, which is now a major concern particularly since its long-term implications remain poorly understood. Revisiting endothelial cell permissivity to SARS-CoV-2 is therefore critical in this setting. We show that SARS-CoV-2, and several strains, do not infect cultured different types of endothelial cells cultured alone or native endothelial cells in situ in human lung tissue. Our findings are in line with the idea that vascular inflammation and thrombosis seen in COVID-19 are independent of direct endothelial cell infection and likely to be mediated by factors released by adjacent infected cells or circulating systemic inflammatory mediators. Our work also suggests that where viremia occurs, SARS-CoV-2 passes through the endothelium, facilitated by loss of barrier function because of local inflammation at the site of infection.

Source: 

Link: https://journals.asm.org/doi/full/10.1128/jvi.01205-25?af=R

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Rebalancing viral and immune #damage versus repair prevents #death from lethal #influenza #infection

 

Abstract

Maintaining tissue function while eliminating infected cells is fundamental, and inflammatory damage plays a major contribution to lethality after lung infection. We tested 50 immunomodulatory regimes to determine their ability to protect mice from lethal infection. Only neutrophil depletion soon after infection prevented death from influenza. This result suggests that the infected host passed an early tipping point after which limiting innate damage alone could not rescue lung function. We investigated treatments that could have efficacy when administered later in infection. We found that partial limitation of viral spread together with enhancement of epithelial repair, by interferon blockade or limiting CD8+ T cell–mediated killing of epithelial cells, reduced lethality. This finding highlights the importance of rebalancing repair and damage processes in the survival of pulmonary infections.

Source: 

Link: https://www.science.org/doi/10.1126/science.adr4635

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A #cattle-derived #human #H5N1 isolate suppresses innate #immunity despite efficient #replication in human respiratory #organoids

 

Abstract

The H5N1 high pathogenicity avian influenza virus (HPAIV) of clade 2.3.4.4b, which spreads globally via wild birds, has become a major public health concern because it can infect a variety of mammals, including humans. In 2024, infection of dairy cattle with H5N1 HPAIV clade 2.3.4.4b was confirmed in the United States, and subsequent human cases were reported. Although these viruses are highly pathogenic in animal models, human infections have generally been mild, revealing a striking discrepancy. Here, we characterized the cattle-derived human H5N1 isolate A/Texas/37/2024 (TX37-H5N1) using three-dimensional human respiratory organoids derived from induced pluripotent stem (iPS) cells. Despite efficient replication, TX37-H5N1 induced minimal interferon and inflammatory cytokine responses. Bulk and single-cell RNA sequencing revealed reduced STAT1-mediated transcriptional activity in TX37-H5N1-infected organoids compared to the historic H5N1 human isolate A/Vietnam/1203/2004. These findings suggest that TX37-H5N1 fails to trigger the strong innate responses, including robust cytokine production, that are typically associated with severe H5N1 disease and are thought to contribute to cytokine storm-medicated pathogenesis. This attenuated response may help explain the discrepancy between the high pathogenicity of TX37-H5N1 in animal models and its mild clinical presentation in humans. While zoonotic influenza risk is often assessed using cell lines or animal models, our study highlights the value of using human respiratory organoids to evaluate human-specific virus-host interactions. This platform provides a complementary tool for assessing the risk of emerging avian influenza viruses.

Competing Interest Statement

The authors have declared no competing interest.

Funder Information Declared

Japan Society for the Promotion of Science, JP24K09264

Japan Agency for Medical Research and Development, JP223fa627005, JP243fa627003h0003, JP24gm1810009, JP223fa627002, JP233fa827018

Japan Agency for Medical Research and Development, JP21gm1610005, JP22gm1610010

Japan Science and Technology Agency, JPMJMS2025

Takeda Science Foundation, https://ror.org/02y123g31

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.11.02.684669v1

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Maternal #Influenza A Virus #Infection Induces Antiviral and Immune Dysregulation in the #Placenta and #Fetus Without Vertical Transmission

 

Abstract

Influenza A virus (IAV) infection during pregnancy is associated with stillbirth and preterm birth, possibly by disrupting placental and fetal immunity. To investigate this, pregnant pigtail macaques were inoculated with IAV [A/California/07/2009 (H1N1)] and examined at necropsy 5 days post-infection (N=11) versus uninfected controls (N=16). Stillbirth occurred in 18% of infected pregnancies but not in controls. While vertical transmission was not observed, low levels of viral RNA were detected in two placentas. Maternal IAV infection was associated with increased placental IL-1β and IFN-β levels and an upregulated type I interferon and integrated stress transcriptional response. Fetuses exposed to IAV had greater frequencies of innate immune cells in lymph nodes and CD4+ T cells in lungs. These results suggest that placental and fetal immune environments undergo immune activation independent of the severity of maternal lung infection. Influenza vaccination during pregnancy may protect against potentially harmful effects on fetal development.

Competing Interest Statement

The authors have declared no competing interest.

Funder Information Declared

National Institutes of Health, https://ror.org/01cwqze88, AI164588, AI176777, AI007509

Foundation for the National Institutes of Health, https://ror.org/00k86s890, OD010425, TR002318, GM007266, OD011123

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.10.06.675688v1

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Repeated #oral #exposure to #H5N1 #influenza virus in pasteurized #milk does not cause adverse responses to subsequent influenza #infection

 

Abstract

In March 2024, a highly pathogenic avian influenza H5N1 (HPAI) clade 2.3.4.4b virus was identified in US dairy cows, with spillover to cats, poultry, and humans. Up to 30% of commercial pasteurized milk tested contained viral genome copies. The impact of residual viral remnants on host immunity is unknown. Orally ingested proteins can stimulate gut-associated lymphoid tissues, potentially inducing tolerance and altering responses to later infection. We found that milk pasteurization fully inactivated pandemic H1N1 and bovine H5N1 influenza viruses yet preserved hemagglutinin (HA) protein integrity. In mice, repeated oral exposure to inactivated virus did not alter mortality after H5N1 virus challenge. Preliminary data showed that naïve mice exposed to improperly pasteurized milk containing live H5N1 virus developed lethal infection, whereas prior H1N1 infection conferred protection. Mice with preexisting H1N1 immunity remained protected when challenged with bovine H5N1 virus after exposure to H5N1 pasteurized in milk. These findings suggest that pasteurized milk containing inactivated H5N1 virus poses minimal health risks.

Source: Science Advances, https://www.science.org/doi/10.1126/sciadv.aeb3906

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#Autoantibodies in #longCOVID: a systematic #review

 

Summary

Post-COVID-19 condition (also known as long COVID) affects a substantial proportion of individuals who have been infected with SARS-CoV-2, profoundly affecting their daily lives and work. Diagnosis and prognosis of long COVID are complex and hindered by heterogeneous symptoms and the absence of validated biomarkers. This systematic review synthesises current evidence on the association between autoantibodies and long COVID, with the goal of evaluating their prognostic and diagnostic utility. Studies published in the PubMed and MEDLINE databases between Jan 1, 2020, and June 10, 2025, were considered. Study selection and quality assessment were done independently by two researchers. Of the 1113 publications screened, 44 studies met the inclusion criteria, with a total of 7571 participants, including 3372 individuals with long COVID. 31 (71%) studies reported an association between autoantibodies and long COVID; however, there was substantial heterogeneity in study design, type and timing of antibody measurements, and long COVID definitions. Several autoantibodies have been associated with long COVID occurrence, symptoms, and severity. Antinuclear antibodies, and autoantibodies targeting G protein-coupled receptors and chemokines, have emerged as potential biomarkers for aiding in the diagnosis, prognosis, and assessment of disease severity in long COVID. However, larger studies are needed to confirm the diagnostic and prognostic utility of these autoantibodies in the context of long COVID.

Source: Lancet Infectious Diseases, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(25)00411-6/abstract?rss=yes

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Single-Cell #Network #Analysis Identifies CLEC4E as a Key Mediator of Proinflammatory mDC Responses in #Influenza #Infection

 

Abstract

The severity of influenza is often driven by an excessive host immune response rather than the virus itself, yet the key molecular drivers within specific immune cells remain poorly understood. While recent single-cell RNA sequencing studies have successfully identified immune populations involved, they have largely not identified the upstream drivers modulating their pro-inflammatory functions. Here we employed an integrated single-cell co-expression network to address this gap. Our analysis identified myeloid dendritic cells (mDCs) as central to pro-inflammatory response during infection. Through a multi-layered key driver analysis, we pinpointed C-type lectin, CLEC4E as a top candidate modulating this pathological inflammatory response. The role of CLEC4E was confirmed in an independent single-cell dataset from influenza-infected patients and further validated in vivo. Pharmacological inhibition of CLEC4E in a murine influenza model significantly reduced disease severity and lower viral titers in the lungs. This study not only clarifies that CLEC4E overexpression in mDCs contributes to pro-inflammatory signaling pathways influencing influenza severity but also shows the power of single-cell network approaches to uncover novel and robust therapeutic targets hidden within complex immune responses.

Competing Interest Statement

The M.S. laboratory has received unrelated funding support in sponsored research agreements from Phio Pharmaceuticals, 7Hills Pharma, ArgenX NV, Ziphius and Moderna.

Funder Information Declared

NIH Common Fund, R21AI149013, R01AI170112, U01AG088351

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.08.21.671587v1

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