ETIDIOH - NEW

Abstract Frequent SARS-CoV-2 vaccination in vulnerable populations has raised concerns that this may contribute to T cell exhaustion , which could negatively affect the quality of immune protection. Herein, we examined the impact of repeated SARS-CoV-2 vaccination on T cell phenotypic and functional exhaustion in frail older adults in long-term care (n = 23), individuals on immunosuppressive drugs (n = 10), and healthy adults (n = 43), in Canada . Spike-specific CD4+ and CD8+ T cell levels did not decline in any cohort following repeated SARS-CoV-2 vaccination, nor did the expression of exhaustion markers on spike-specific or total T cells increase. T cell production of multiple cytokines (i.e. polyfunctionality) in response to the spike protein of SARS-CoV-2 did not decline in any cohort following repeated vaccination. None of the cohorts displayed elevated levels of terminally differentiated T cells following multiple SARS-CoV-2 vaccinations. Thus, repeated SARS-CoV-2 vaccination was...

Abstract The 2024 outbreak of highly pathogenic avian influenza virus (HPAIV) H5N1 in U.S. dairy cattle presented an unprecedented scenario where the virus infected bovine mammary glands and was detected in milk , raising serious concerns for public health and the dairy industry. Unlike previously described subclinical influenza A virus (IAV) infections in cattle, H5N1 infection induced severe clinical symptoms , including respiratory distress, mastitis, and abnormal milk production . To understand the host immune responses and changes, particularly in the mammary gland, we performed single-cell RNA sequencing analysis on bovine milk somatic cells (bMSCs) in vitro exposed to an H5N1 isolate from an infected dairy farm. We identified ten distinct cell clusters and observed a shift toward type-2 immune responses , characterized by T cells expressing IL13 and GATA3 , and three different subtypes of epithelial cells based on the expression of genes associated with milk production. Our stud...

Abstract Fever during influenza A virus (IAV) infection is triggered by the innate immune response . Various factors contribute to this response, including IAV mini viral RNAs (mvRNA), which trigger RIG-I signaling when their replication and transcription are dysregulated by template loops (t-loop). It is presently not well understood whether the fever response to IAV infection impacts subsequent viral replication and innate immune activation . Here we show that IAV infection at temperatures that simulate fever leads to increased mvRNA synthesis and antiviral signaling . Mathematical modeling and experimental analyses reveal that differential IAV nucleoprotein and RNA polymerase production underlies the increased mvRNA level. Moreover, at the higher infection temperature mvRNAs with dysregulating t-loops contribute most to the innate immune activation. We propose that fever during IAV infection can establish a positive feedback loop in which elevated aberrant RNA synthesis and innate i...

Summary Background Evidence from randomised clinical trials (RCTs) of Janus kinase (JAK) inhibitors —compared with usual care or placebo—in adults treated in hospital for COVID-19 is conflicting. We aimed to evaluate the benefits and harms of JAK inhibitors compared with placebo or usual care and whether treatment effects differed between prespecified participant subgroups. Methods For this systematic review and individual participant data meta-analysis (IPDMA), we searched Medline via Ovid, Embase via Elsevier, the Cochrane Central Register of Controlled Trials , the Cochrane COVID-19 Study Register, and the COVID-19 L·OVE Platform, including backward and forward citation searching (last search Nov 28, 2024), for RCTs (unpublished or published in any format and any language) that randomly assigned adults (aged ≥16 years) admitted to a hospital due to COVID-19 to receive either a JAK inhibitor (any type) or no JAK inhibitor (ie, received site-specific standard of care with or without p...

Abstract Infections by influenza A virus (IAV) are a significant cause of global mortality . The pathogenesis of the infection is usually studied in terms of direct viral-induced damage or the overreactive immune response that continues after the virus is cleared. However, factors such as the initial infectious dose , the early response after infection in different cell types, and the presence of autoantibodies for relevant antiviral cytokines like type I IFNs seem to influence the course of the infection and lead to fatal outcomes . In this article, we address the current knowledge about the early events during influenza virus infection, which are important for their participation in influenza-derived pathogenesis. Source: Viruses,  https://www.mdpi.com/1999-4915/17/5/694 ____

ABSTRACT Sporadic human infections of avian influenza virus (AIV) raise significant public health concerns . A critical factor limiting the transmission of AIVs is the shift in receptor-binding preference from Siaα2,3 to Siaα2,6. To reveal the adaptive selection dynamics during the host adaptation process of AIVs, this study generated a viral library with random mutations in the HA gene of the H9N2 strain . Upon passaging the viral library in chickens and mice , the predominantly selected variants exhibited a preference for Siaα2,3 receptors . Notably, the wild-type strain remained dominant in both inoculated and direct-contact chickens, while variants with the ΔL226/R229I substitutions were preferentially selected in mice. Ferrets have a predominance of Siaα2,6 in their respiratory tract. As expected, the variant harboring the N289D mutation, which prefers Siaα2,6 binding, was enriched during in vivo passaging in ferrets . The mice-adapted variant with the ΔL226/R229I mutations causes...

Abstract Influenza A(H7N9) virus showed high pathogenicity in humans when it emerged in 2013. Cigarette smoke (CS) causes pulmonary diseases including bronchitis, emphysema, and lung cancer . Although habitual smoking is thought to increase the risk of severe seasonal influenza virus infection, its effect on A(H7N9) virus infection is poorly understood . Here, we employed a mouse model of long-term exposure to CS to investigate the effect of CS on the pathogenicity of A(H7N9) virus infection. Unexpectedly, body weight loss for mice exposed to CS was milder than that for mock-treated mice upon A(H7N9) virus infection. CS exposure improved the survival rate of A(H7N9) virus-infected mice even though virus titers and pathological changes in the lungs were not significantly different between CS-exposed and control mice. Microarray analysis showed that CS-exposure activates cytokine/chemokine activity , immune response, and cell cycle activities that resemble reactivities against A(H7N9) vi...

Abstract Exaggerated inflammation and cytokine storm are hallmark features of influenza A virus (IAV)-induced respiratory diseases. While previous studies unequivocally demonstrated the pathophysiological consequences (multiorgan failure) of IAV-associated cytokine storm, it remains unknown if IAV-induced systemic inflammation impacts the fitness and differentiation of immune cells from hematopoietic stem cells (HSCs). Our data on lethal IAV-infected C57BL/6 wildtype mice after 10 days of infection indicated reduced monocyte- and lymphocyte- counts in the peripheral blood, and overall cellularity of spleen, thymus and lymph nodes . IAV- infection resulted in increased numbers of myeloid cells, CD8+ T cells, alveolar macrophages (AVMs), CD11b+ dendritic cells (DCs) & plasmacytoid DCs (pDCs), whereas decreased frequencies of CD103+ DCs, in the lungs of IAV-infected mice. Analysis of spleen and draining lymph nodes indicated reduced absolute numbers of B cells, T cells, monocytes and ...

Summary Background SARS-CoV-2 infection leads to post-acute sequelae that can affect nearly every organ system , including the immune system . However, whether an infection with SARS-CoV-2 is associated with increased risk of future infections with other pathogens is not yet fully characterised. In this study, we aimed to test the association between a positive test for COVID-19, compared with a negative test, and rates of future infections with other pathogens. Methods We used the US Department of Veterans Affairs health-care databases to build a spatiotemporally aligned cohort of 231 899 people with a positive COVID-19 test and 605 014 with a negative COVID-19 test (test-negative control group) between Nov 1, 2021, and Dec 31, 2023. We first did a discovery approach to map the associations between those with a positive COVID-19 test versus a negative test and laboratory-based outcomes of infectious illnesses. We then compared rates of a prespecified set of infectious disease outcomes...

Abstract An exhausted antiviral immune response is observed in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-SARS-CoV-2 syndrome , also termed long COVID . In this study, potential mechanisms behind this exhaustion were investigated. First, the viral load of Epstein–Barr virus (EBV), human adenovirus (HAdV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV6), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was determined in sputum samples (n = 29) derived from ME/CFS patients (n = 13), healthy controls (n = 10), elderly healthy controls (n = 4), and immunosuppressed controls (n = 2). Secondly, autoantibodies (autoAbs) to type I interferon (IFN-I) in sputum were analyzed to possibly explain impaired viral immunity. We found that ME/CFS patients released EBV at a significantly higher level compared to controls (p = 0.0256). HHV6 was present in ~50% of all participants at the same level. HAdV was detected in two cases with immunosuppression an...

Abstract The novel H10N3 avian influenza virus (AIV) has infected four individuals since 2021 and caused severe respiratory damage , posing a significant threat to public health . However, its pathogenic mechanisms remain poorly understood. Our findings revealed that H10N3 infection induces severe lung damage and causes death in mice , even at low doses. The elevated levels of multiple pro-inflammatory factors in the bronchoalveolar lavage fluid were significantly increased during infection, displaying hallmarks of a cytokine storm . Transcriptome sequencing further revealed systematic activation of inflammation-related pathways, predicting that viral infection induces multiple forms of programmed cell death , including apoptosis, pyroptosis, and necroptosis . Protein-level validation showed that the activation of key cell death markers, including Caspase-3, GSDMD, and MLKL , significantly increased as the infection progressed, with their dynamic changes correlating strongly with the e...

ABSTRACT The COVID-19 pandemic has greatly enhanced our understanding of CD8+ T cell immunity and their role in natural infection and vaccine-induced protection. Rapid and early SARS-CoV-2- specific CD8+ T cell responses have been associated with efficient viral clearance and mild disease . Virus-specific CD8+ T cell responses can compensate for waning, morbidity-related , and iatrogenic reduction of humoral immunity. After infection or vaccination, SARS-CoV-2-specific memory CD8+ T cells are formed, which mount an efficient recall response in the event of breakthrough infection and help to protect from severe disease. Due to their breadth and ability to target mainly highly conserved epitopes, SARS-CoV-2-specific CD8+ T cells are also able to cross-recognize epitopes of viral variants , thus maintaining immunity even after the emergence of viral evolution. In some cases, however, CD8+ T cells may contribute to the pathogenesis of severe COVID-19. In particular, delayed and uncontrolle...

Abstract In 2020–2021, a “mysterious illness” struck Senegalese fishermen , causing severe acute dermatitis in over one thousand individuals following exposure through drift-net fishing activity . Here, by performing deep analysis of the environmental samples we reveal the presence of the marine dinoflagellate Vulcanodinium rugosum and its associated cyclic imine toxins . Specifically, we show that the toxin PortimineA, strongly enriched in environmental samples, impedes ribosome function in human keratinocytes , which subsequently activates the stress kinases ZAKα and P38 and promotes the nucleation of the human NLRP1 inflammasome, leading to the release of IL-1β/IL-18 pro-inflammatory cytokines and cell death . Furthermore, cell-based models highlight that naturally occurring mutations in the P38-targeted sites of human NLRP1 are unable to respond to PortimineA exposure. Finally, the development and use of human organotypic skins and zebrafish models of PortimineA exposure demonstrat...