Effects of prolonged #SARS-CoV2 #spike protein #exposure in #longCOVID and a mouse model of the disease

 

ABSTRACT

We addressed the question: can the SARS-CoV2 spike protein persist in ACE2+ endothelia in the CNS/other sites and induce a prolonged microvasculature injury syndrome? People who died from COVID-19, with age-matched controls, and people with long COVID with symptoms persisting from 1-5 years, with controls of people who had recovered from COVID-19, were studied. Also compared were WT mice injected with the spike protein sacrificed at day 5 versus 1.5 months. The ACE2+ microvasculature density in the CNS increased 19-fold in the mice exposed to spike for 1.5 months. Human fatal COVID-19 cases showed an ACE2+ CNS density of 13.2/3.9 versus 2.1/0.9 for the controls. Long Covid cases showed an ACE2 microvasculature density of 11.9/3.0 versus 3.5/0.9 for the people who recovered from COVID (each p value < 0.001). Viral spike microvasculature density in the CNS was similar in the fatal COVID-19 cases (6.9/2.1) and mice (7.0/4.0) and in the skin of long-COVID cases (6.0/1.9) and less in people who recovered from COVID-19 (0.9/0.3) (each p < 0.001). Microvasculature collagen 1 deposition was only evident in fatal COVID, long COVID, and in the mice exposed to S1 for 1.5 mo. Thus, SARS-CoV2 spike (S1) protein can persist for months/years with an associated microvasculature pro-inflammatory state and a restrictive fibrosing microangiopathy; and exposure to high dose S1 markedly increases ACE2 endothelial density.

Source: 

Link: https://doi.org/10.1016/j.ajpath.2026.09.009

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Strong #Protein #Responses to Acute #Infection Control General Post-Viral #Sequelae and #SARS-CoV-2-specific #Neurocognitive Sequelae

 

Abstract

After serious infections, many survivors fully recover while others face persistent symptoms including neurocognitive dysfunction, cardiopulmonary instabilities and disabling fatigue, classified broadly as Post-Acute Infection Syndromes (PAIS). Post-Acute Sequelae of COVID19 (PASC) is one special case. To test whether acute infection initiates PAIS, we analyzed proteins in 173 saliva samples collected during severe respiratory viral infections and tracked patient outcomes for five years. We discovered 44 proteins, all derived from interferon stimulated genes, that respond strongly to acute infection. Rates of post-acute syndromes were similar regardless of infection, but the types of Sequelae differed by virus. High expression of 19 proteins predict low General Sequelae rates across all viruses. High expression of 23 overlapping proteins predict low Neurocognitive Sequelae rates only with SARS-CoV-2 infections. We propose that low expressions of these proteins, which control viral replication, innate immunity, and secondary autoimmunity, combine to precipitate PAIS and PASC.

Competing Interest Statement

Theodore G. Liou, Judy L Jensen and Kristyn A Packer received research funding from Anagram, Aridis, BioMX, Calithera, Clarametyx, Judy L Jensen and Kristyn A Packer received research funding from Anagram, Aridis, BioMX, Calithera, Clarametyx, Gilead, Insmed, Laurent, Novartis, Sionna, SpliSense, the US Cystic Fibrosis Foundation's Therapeutic Development Network and Vertex for performance of clinical studies during the study and manuscript preparation period. Theodore Liou is a member and Rhonda Szczesniak is vice-chair of the Cystic Fibrosis Foundation Clinical Research Committee. Theodore Liou and Frederick Adler, through the University of Utah, are named as inventors on the following patent applications related to the proteins identified in this manuscript: (1) a provisional patent application titled "DIAGNOSTICS AND TREATMENTS FOR ACUTE AND POST-VIRAL DISEASE BASED ON INNATE IMMUNE RESPONSES TO SARS-COV-2 INFECTION," serial number 63/792,687, filed 4/22/2025; (2) a provisional patent application titled "ADDITIONAL INNATE IMMUNE RESPONSES WITH DIAGNOSTIC AND TREATMENT POTENTIAL FOR POST-ACUTE SEQUELAE OF COVID19 SYNDROME AND FOR POST-ACUTE INFECTION SYNDROME," serial number 63/979,883, filed 2/10/2026; (3) a Patent Cooperation Treaty (PCT) application titled "METHODS FOR PREDICTING POST-ACUTE SEQUELAE OF VIRAL INFECTIONS USING INTERFERON STIMULATED GENE PROTEINS," serial number PCT/US2026/024520, filed 4/21/2026, which incorporates subject matter from (1) and (2); and (4) a provisional patent application titled "ADDITIONAL ACUTELY EXPRESSED PROTEINS PROTECTIVE AGAINST NEUROCOGNITIVE AND GENERAL POST-VIRAL SEQUELAE," serial number 64/102,461, filed 6/30/42026. The applicant on all applications is the University of Utah.

Source: 

Link: https://www.medrxiv.org/content/10.64898/2026.08.27.26361488v2

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Integrated in vivo and transcriptomic analyses of lethal #Oropouche virus #infection reveal suppression of pathogenic host responses by #antiviral therapy

 

Abstract

Oropouche virus (OROV) is an emerging arbovirus responsible for large outbreaks of febrile illness in Central and South America, with increasing reports of severe neurological disease and fatal outcomes. Despite its growing public health impact, no approved antiviral therapies or vaccines are currently available. Here, we show that favipiravir, a broad-spectrum nucleoside analogue, robustly suppresses OROV replication and disease in vivo. In a lethal Syrian hamster model, favipiravir treatment provided complete protection against OROV infection, preventing viral dissemination to peripheral organs and the central nervous system, and remained highly effective when administration was initiated after infection. In contrast, insufficient antiviral control resulted in viral neuroinvasion and fatality. To define host responses associated with OROV pathogenesis and their modulation by antiviral therapy, we performed transcriptomic profiling of liver and brain tissues. OROV infection induced interferon-driven inflammatory programs accompanied by marked disruption of metabolic and tissue homeostatic pathways, whereas these transcriptional signatures were largely abrogated by favipiravir treatment. Together, our findings identify favipiravir as a potent antiviral candidate against OROV and provide the first in vivo, tissue-resolved transcriptomic framework of OROV infection, linking effective viral suppression with the prevention of neuroinvasion and pathogenic host responses. These results highlight antiviral intervention as a viable strategy to mitigate OROV-associated disease and mortality.

Source: 

Link: https://doi.org/10.1371/journal.ppat.1014647

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Persistent #influenza A #RNA detection in a #fatal #pediatric case of influenza-associated #encephalopathy

 

Abstract

Influenza-associated encephalopathy (IAE) is a life-threatening complication of influenza. We report a case of a 9-year-old boy diagnosed with fulminant IAE. The patient received life-sustaining support, intensive immunomodulatory therapy, and antiviral therapy. Following an initial single dose of baloxavir marboxil, persistent influenza A (H3N2) RNA detection prompted a multi-targeted antiviral regimen (oseltamivir, baloxavir marboxil, peramivir, and onradivir) as salvage therapy. Nevertheless, influenza A RNA remained detectable for more than 1 month, potentially reflecting severe neurological injury, immunosuppression, and impaired airway clearance.

Source: 

Link: https://doi.org/10.1016/j.jiph.2026.103380

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N70S/Y155H Combined #Mutation of #Neuraminidase of Avian #Influenza #H9N2 Virus confers #oseltamivir and #zanamivir #resistance and pathogenicity to Mice

 

Highlights

    • H9N2 viruses recently circulating in China harbors novel N70S/Y155H dual mutations in N2;

    • H9N2 viruses with N70S/Y155H mutations exhibit high pathogenicity to BALB/c mice.

    • N70S/Y155H linked mutations in N2 confer resistance to oseltamivir and zanamivir, rather than peramivir.

    • Neuraminidase inhibitors exhibited limited efficacy on H9N2 virus with novel N70S /Y155H dual mutations.

Abstract

Recently, H9N2 avian influenza virus (AIV) poses a significant threat to both the poultry industry and public health. Therefore, investigating the impact of its neuraminidase mutations on susceptibility to neuraminidase inhibitors (NAIs) is of great importance for clinically preventing potential cross-species transmission of H9N2. In this study, our results revealed that NAI resistance-related mutations of most H9N2 viruses isolated from China during 1998 to 2024 mainly occurred at positions N70S, E119A/D/G/V, Q133K, Q136A, D151E, Y155H, I222V, R224K, E276D, R292K, N294S, and R371K. Among them, the combined N70S and Y155H mutations are common characteristics of H9N2 viruses circulating in recent years. In vivo experiments demonstrated that these H9N2 viruses harboring the combined N70S and Y155H mutations exhibit high pathogenicity to BALB/c mice without prior adaption. In vitro neuraminidase inhibition assays confirmed that these H9N2 viruses bearing the N70S/Y155H mutations exhibited greater reduced inhibition than their counterparts bearing the N70S or Y155H single mutation to oseltamivir and zanamivir, but remained highly sensitive to peramivir. Notably, the in vivo protective effect of NAIs against H9N2 virus with combined N70S and Y155H mutations is limited, possibly due to the restricted ability of these drugs to ameliorate the excessive inflammatory responses. Therefore, there is an urgency to strengthen research on epidemiological surveillance and prevention strategies for avian influenza H9N2 harboring these mutations.

Source: 

Link: https://doi.org/10.1016/j.antiviral.2026.106540

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Human #Adenovirus B3–Induced Immune #Thrombocytopenia and #Thrombosis

 

{Extract}

(...)

We report here the case of a previously healthy 12-year-old boy in whom virus-induced immune thrombocytopenia and thrombosis developed approximately 1 week after the onset of respiratory infection symptoms. Immune thrombocytopenia was suspected, and prednisolone therapy (30 mg daily) was started at the referring hospital. 

(...)

Source: 

Link: https://www.nejm.org/doi/full/10.1056/NEJMc2605960?query=TOC

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#Pathogenesis and natural history of the #Bundibugyo species of #Orthoebolavirus in nonhuman #primates

 

Abstract

The current outbreak of Bundibugyo virus (BDBV) in Africa is a global public health concern particularly as there are no licensed medical countermeasures (MCM). Well characterized animal models that accurately replicate human BDBV infection are needed to develop effective MCM. We exposed 21 cynomolgus monkeys (CM) to BDBV to examine the progression and natural history of BDBV disease (BVD). BVD was more protracted than reported for Ebola and Sudan infection in CM with a lower lethality rate of 67% consistent with lower human BVD mortality rates. IHC and spatial proteomics identified CD209+, CD68+, and/or HLA-DR+ macrophages and dendritic cells as early targets of BDBV. These infected cells frequently colocalized with fibrin and infiltrating MPO+ neutrophils and S100A9+ myeloid-derived suppressor cells, consistent with the development of an active inflammatory response and early coagulopathy. Transcriptomic and proteomic analyses of the circulating immune response correspondingly reflected a cytokine-driven hyperinflammatory state in CM that succumbed to disease. Surviving animals resolved systemic inflammation by the study endpoint; however, BDBV antigen was identified in immune privileged tissues with lesion-associated inflammation aligning with known post-Ebola sequela in humans. This data should assist in identifying weaknesses in the disease course that can be exploited to develop new MCM.

Competing Interest Statement

The authors have declared no competing interest.

Funder Information Declared

National Institute of Allergy and Infectious Diseases, https://ror.org/043z4tv69, U19AI109945

The University of Texas Medical Branch at Galveston, https://ror.org/016tfm930, N/A

Source: 

Link: https://doi.org/10.64898/2026.08.10.743937

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Assessment of immune #response induced by ChAdOx1 nCoV-19, Sputnik V, and BNT162b2 #vaccines during #COVID19 #outbreak in #Mexican population: Gene expression of the #cytokine storm

 

Highlights

    • The molecular immune response triggered by vaccines against COVID-19 was analyzed.

    • The evaluated genes were ACE2, CD79B, TMPRSS2, CTSB, FCGR3A and MB-1.

    • These vaccines induce a protective immune response through various mechanisms.

    • Vaccines regulate the immune response through pro- and anti-inflammatory cytokines.

Abstract

Introduction

COVID-19 vaccines using different technological platforms may induce distinct molecular responses. Characterizing gene-expression patterns after vaccination and in fatal COVID-19 may identify pathways associated with vaccination and severe disease.

Objective

To compare immune-, inflammatory-, and SARS-CoV-2-entry-related gene expression after AstraZeneca, Pfizer, or Sputnik V vaccination and with unvaccinated fatal COVID-19.

Materials and methods

Eighty Mexican adults were included: AstraZeneca (n = 19), Pfizer (n = 20), Sputnik (n = 21), and unvaccinated fatal COVID-19 (n = 20). Expression of 11 genes was measured by qPCR at days 30 (D30) and 60 (D60) after vaccination.

Statistical analysis

Longitudinal differences were analyzed by two-way repeated-measures ANOVA. Comparisons with fatal COVID-19 were exploratory. Benjamini–Hochberg correction controlled false discovery rate at 5%.

Results

No differences among vaccines were detected at D30. At D60, IL-10, IL-2, and CD79A differed among selected vaccine groups. Longitudinally, FCGR3A decreased in AstraZeneca and Sputnik, ACE2 decreased in Pfizer and Sputnik, and TMPRSS2 increased in Sputnik. Fatal COVID-19 showed predominantly higher expression of several genes than vaccinated groups. Notably, IL-2 and ACE2 were consistently higher in fatal COVID-19 than in all vaccinated groups at both time points.

Discussion and conclusions

Post-vaccination transcriptional profiles were dynamic, with selected differences emerging at D60, whereas fatal COVID-19 exhibited a distinct profile characterized predominantly by higher expression of immune-, inflammatory-, and viral-entry-related genes. Consistent IL-2 and ACE2 differences highlight molecular pathways potentially associated with severe disease. The observational design, however, precludes causal attribution to vaccination.

Perspectives

Longitudinal studies with appropriate controls are needed to establish the biological significance of these transcriptional patterns.

Source: 

Link: https://doi.org/10.1016/j.meegid.2026.106025

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Acute #Protein Responses Control #SARS-CoV-2-specific #Neurocognitive and General Post-Viral #Sequelae

 

Abstract

Post-acute infection syndromes (PAIS) follow viral syndromes including post-acute sequelae of COVID19 (PASC) which complicates 10-25% of SARS-CoV-2 infections. These syndromes lack precise explanatory mechanisms. We studied 173 human saliva proteomes during respiratory viral syndromes, seeking associations between 44 clinically-relevant protein expression patterns and subsequent sequelae counts. Exploratory models adjusted by extensive clinical annotations found interactions between 23 acutely-responsive proteins and SARS-CoV-2 infection that inversely predicted subsequent neurocognitive sequelae. An overlapping 19 acutely-responsive proteins during any acute respiratory viral syndrome inversely predicted general fatigue-related sequelae. Altogether, 29 proteins, derived from interferon stimulated genes (ISG), were uniformly beneficial, including 13 predictive of both neurocognitive and general sequelae. The proteins suggested both shared early pathobiology and virus-specific protective responses that shaped resolution of acute disease and different PAIS. Acutely elevated protective ISG proteins associated with reduced post-viral symptoms identify investigational starting points for novel mechanisms, diagnostics and therapeutics for PASC and PAIS.

Competing Interest Statement

Theodore G. Liou, Judy L Jensen and Kristyn A Packer received research funding from Anagram, Aridis, BioMX, Calithera, Clarametyx, Gilead, Insmed, Laurent, Novartis, the US Cystic Fibrosis Foundation′s Therapeutic Development Network and Vertex for performance of clinical studies during the study period. Bricelyn H Strauch maintains the copyright for Figure 3. Theodore Liou and Frederick Adler, through the University of Utah, are named as inventors on the following patent applications related to the proteins identified in this manuscript: (1) a provisional patent application titled ″DIAGNOSTICS AND TREATMENTS FOR ACUTE AND POST-VIRAL DISEASE BASED ON INNATE IMMUNE RESPONSES TO SARS-COV-2 INFECTION,″ serial number 63/792,687, filed 4/22/2025; (2) a provisional patent application titled ″ADDITIONAL INNATE IMMUNE RESPONSES WITH DIAGNOSTIC AND TREATMENT POTENTIAL FOR POST-ACUTE SEQUELAE OF COVID19 SYNDROME AND FOR POST-ACUTE INFECTION SYNDROME,″ serial number 63/979,883, filed 2/10/2026; (3) a Patent Cooperation Treaty (PCT) application titled ″METHODS FOR PREDICTING POST-ACUTE SEQUELAE OF VIRAL INFECTIONS USING INTERFERON STIMULATED GENE PROTEINS,″ serial number PCT/US2026/024520, filed 4/21/2026, which incorporates subject matter from (1) and (2); and (4) a provisional patent application titled ″ADDITIONAL ACUTELY EXPRESSED PROTEINS PROTECTIVE AGAINST NEUROCOGNITIVE AND GENERAL POST-VIRAL SEQUELAE,″ serial number 64/102,461, filed 6/30/2026. The applicant on all applications is the University of Utah.

Source: 

Link: https://www.medrxiv.org/content/10.64898/2026.08.27.26361488v1

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A mouse #monoclonal #antibody against #H7N9 #influenza virus cross-react with #human #platelets

 

Highlights

    • H7N9–98 mAb specifically binds human platelets and targets a ~60 kDa platelet protein.

    • H7N9 virus induces ITP via molecular mimicry with platelet antigens.

    • H7N9 virus-related ITP correlates with disease severity.

Abstract

Objective

To investigate the association and potential mechanisms between H7N9 influenza virus infection or vaccination and immune thrombocytopenia (ITP), providing foundational data for the prevention and treatment of related ITP.

Methods

Using laboratory-prepared anti-H7N9 influenza virus monoclonal antibodies (mAbs) (H7N9-98 and H7N9-120) as research subjects, the interactions between these antibodies and human platelets were analyzed through Western blotting (WB), immunohistochemistry (IHC), and immunofluorescence (IF) techniques.

Results

The mAb H7N9-98 exhibited specific binding to human platelets, showing positive results in both IHC and IF assays. Western blotting results demonstrated that this antibody could specifically recognize approximately 60 kDa human platelet proteins. The isotype control mAb H7N9-120 did not exhibit the aforementioned binding reactions, with all test results being negative.

Conclusion

These findings suggest that the specific antibodies induced by the H7N9 virus may mediate platelet damage through cross-reactivity with platelet autoantigens. This mechanism warrants further investigation to provide experimental evidence for the pathogenesis of secondary ITP associated with H7N9 infection.

Source: 

Link: https://www.sciencedirect.com/science/article/pii/S1567134826001346?via%3Dihub

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Cardiopulmonary Failure in #Hantavirus Disease: Mechanisms, Recognition, and #ECMO-Based Management

 

Abstract

Background: 

Hantavirus pulmonary syndrome (HPS), also designated hantavirus cardiopulmonary syndrome, is caused by New World hantaviruses, principally Sin Nombre virus in North America and Andes virus in South America. The syndrome is characterized by rapidly progressive noncardiogenic pulmonary edema and myocardial depression, with case fatality rates of 25% to 40%. A 2026 outbreak aboard an expedition cruise ship in the South Atlantic, comprising 13 cases and three deaths, confirmed that Andes virus can be transmitted between humans in a confined setting remote from the rodent reservoir. 

Methods: 

Virological, pathophysiological, clinical, and therapeutic aspects of HPS were reviewed, with particular emphasis on cardiopulmonary mechanisms. Sources were identified through PubMed, Scopus, and Google Scholar, with priority given to original research articles, clinical series, and controlled trials published through 2025. Literature published in English and Spanish was included. 

Results: 

Pathogenic hantaviruses enter endothelial cells and platelets via αvβ3 integrins, disrupting the VEGF-VEGFR2 signaling axis and rendering endothelial cells hypersensitive to physiological VEGF concentrations. Expansion of CD8+ T cells and activated macrophages releases TNF-alpha, IFN-gamma, and nitric oxide, amplifying microvascular permeability and contributing to myocardial depression. Autopsy studies demonstrate direct hantaviral myocarditis with viral antigen in cardiac endothelium and interstitial macrophages. Transpulmonary thermodilution confirms simultaneous hypovolemia, reduced global ejection fraction, and elevated extravascular lung water. Because the incubation period is long and the cardiopulmonary phase is substantially immune-mediated, seroconversion precedes rather than follows clinical deterioration, which preserves the diagnostic utility of IgM serology in a disease that can kill within 48 h. VA-ECMO initiated at the first signs of cardiopulmonary decompensation has reported survival rates approaching 80% in selected experienced centers. No antiviral has demonstrated efficacy in controlled trials during the cardiopulmonary phase, and no licensed vaccine exists. 

Conclusions: 

HPS produces a mixed shock state through increased microvascular permeability, T cell-mediated immunopathology, and direct myocarditis. Management follows a stepwise algorithm: suspected HPS triggers immediate complete blood count with peripheral blood smear and concurrent hantavirus IgM serology and RT-PCR, followed by ICU admission, conservative fluid resuscitation guided by transpulmonary thermodilution, and early contact with an ECMO-capable center at the first sign of rising lactate, falling cardiac index, refractory shock, arrhythmia, or rapid oxygenation failure.

Source: 

Link: https://www.mdpi.com/1999-4915/18/8/915

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Innate Immune Responses Induced by #H9N2 #Influenza A Virus and #Klebsiella pneumoniae Co-Infection

 

Abstract

Klebsiella pneumoniae infection following H9N2 Influenza A virus (IAV) infection causes severe pneumonia. But the underlying pathogenic mechanisms of H9N2 IAV and K. pneumoniae co-infection are complex and need to be further explored. In this study, the lung transcriptomes of mice with H9N2 IAV and K. pneumoniae co-infection were characterized by transcriptomic profiling. As a result, GO enrichment analysis revealed that the differential genes were primarily involved in the activation of immune responses, cellular components of membranes and extracellular spaces, and defense responses against pathogen infections. According to KEGG enrichment, the differentially expressed genes (DEGs) were concentrated in TLR signaling pathways, RLR signaling pathways, TNF signaling pathways and NLRP3 signaling pathways. Furthermore, in vitro cell models were established to investigate the innate immune responses induced by H9N2 IAV and K. pneumoniae CPS co-stimulation. K. pneumoniae CPS stimulation influenced the cytokine profiles of mink lung epithelial cells infected with H9N2 IAV, worsened cell viability, and aggravated apoptosis, indirectly inhibiting H9N2 IAV replication. The findings demonstrated that K. pneumoniae superinfection modulated the innate immune responses induced by H9N2 IAV infection, contributing to its pathogenesis.

Source: 

Link: https://www.mdpi.com/1999-4915/18/8/900

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Virus #reactivation in acute and long #COVID19

 

Abstract

Chronic viral infections are ubiquitous in humans, with individuals carrying multiple viruses that can reactivate during physiological stress, including severe illness1. Notably, SARS-CoV-2 infection has been shown to reactivate chronic viruses such as Epstein–Barr virus and cytomegalovirus, yet the full extent, temporal dynamics and immunological impact of viral reactivation in COVID-19 remain incompletely understood. Here, leveraging multi-omic longitudinal data from 1,154 hospitalized patients with COVID-19 from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, we reveal significant reactivation of Herpesviridae and Anelloviridae during acute COVID-19, with distinct temporal dynamics for different viruses, and demonstrate that reactivation correlates with disease severity, host immune effects and clinical outcomes. Although our results do not establish causation between virus reactivation and clinical outcomes, we highlight the prevalence of chronic viral reactivation during acute COVID-19 and long COVID. Our findings challenge the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression, demonstrating that reactivations occur frequently in immunocompetent individuals during severe illness and in association with increased systemic inflammation. Additionally, we demonstrate persistence of viral reactivation in convalescence, and report an association of Anelloviridae with long COVID. This study provides immune, transcriptomic and metabolomic signatures of viral reactivation that could inform future strategies to prognosticate and treat acute COVID-19 and long COVID.

Source: 

Link: https://www.nature.com/articles/s41586-026-10740-z

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#Losartan and #prednisolone for #postCOVID syndrome and cardiac inflammation: a randomized, double-blind, placebo-controlled trial

 

Abstract

Persistent cardiac symptoms are common in post-COVID syndrome, even without structural heart disease. Evidence implicates immune dysregulation, endothelial dysfunction and low-grade cardiovascular inflammation. Yet no targeted treatment exists. Myoflame-19 is a multicenter, double-blind clinical trial of 279 participants with inflammatory cardiac involvement defined by cardiovascular magnetic resonance, randomized 1:1 to losartan plus prednisolone (n = 139) or matching placebos (n = 140) for 16 weeks. The modified intention-to-treat population comprised 124 and 122 participants. The primary endpoint, change in left ventricular (LV) ejection fraction, was neutral: between-group difference 0.74 percentage points (pp), 95%CI −0.14 to 1.62, p = 0.10, unpaired t-test; supportive baseline-adjusted ANCOVA 0.99, 95%CI 0.15-1.83, p = 0.021. Among prespecified secondary endpoints, several symptom and imaging measures showed numerical differences favoring intervention, including Average Symptom Score components (modified Canadian Chest Pain Scale −4.8 pp, 95%CI −17.3 to 7.6; NYHA class −8.1 pp, −20.6 to 4.3; Long COVID symptom burden −7.7 pp, −18.9 to 3.6), native T1 and T2 values (native T1 −2.46 ms, −8.35 to 3.42; native T2 −0.31 ms, −1.16 to 0.53), and LV end-diastolic volume ( + 1.45 ml/m², −0.09 to 3.00); however, confidence intervals included the null value and these findings should be regarded as hypothesis-generating.Treatment was safe and well-tolerated. These findings indicate a neutral treatment effect on the primary endpoint. They inform targeted immunomodulation and design of future trials in post-COVID syndrome and inflammatory cardiac involvement. Trial registration: EudraCT 2022-001682-12; NCT05619653.

Source: 

Link: https://www.nature.com/articles/s41467-026-75991-w

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#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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