#Age-Dependent #Pathogenesis of #Influenza A Virus #H7N9 Mediated Through #PB1-F2-Induced Mitochondrial DNA Release and Activation of cGAS-STING-NF-κB Signaling

Source: Journal of Medical Virology, https://onlinelibrary.wiley.com/doi/10.1002/jmv.70062

ABSTRACT
Exactly why human infection of avian influenza A virus H7N9 causes more severe disease in the elderly remains elusive. In this study, we found that H7N9 PB1-F2 is a pathogenic factor in 15–18-month-old BALB/C mice (aged mice) but not in 6–8-week-old young adult mice (young mice). Recombinant influenza A virus with H7N9 PB1-F2-knockout was less pathogenic in aged mice as indicated with delayed weight loss. In contrast, survival of young mice infected with this virus was diminished. Furthermore, tissue damage, inflammation, proinflammatory cytokine and 2′3′-cGAMP production in the lung were less pronounced in infected aged mice despite no change in viral titer. cGAS is known to produce 2′3′-cGAMP to boost proinflammatory cytokine expression through STING-NF-κB signaling. We found that H7N9 PB1-F2 promoted interferon β (IFNβ) and chemokine gene expression in cultured cells through the mitochondrial DNA-cGAS-STING-NF-κB pathway. H7N9 PB1-F2 formed protein aggregate and caused mitochondrial cristae collapse, complex V-dependent electron transport dysfunction, reverse electron transfer-dependent oxidized mitochondrial DNA release to the cytoplasm and activation of cGAS-STING-NF-κB signaling. PB1-F2 N57 truncation, which is frequently observed in human circulating strains, mitigated H7N9 PB1-F2-mediated mitochondrial dysfunction and cGAS activation. In addition, we found that PB1-F2 of pathogenic avian influenza viruses triggered more robust cGAS activation than their human-adapted descendants. Our findings provide one explanation to age-dependent pathogenesis of H7N9 infection.

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#aH7n9 #abstract #animalModels #avianInfluenza #AVIANINFLUENZA #birdFlu #h5n1 #health #news #research #viralPathogenesis

Sustained #vaccine #exposure elicits more rapid, consistent, and broad #humoral immune responses to multivalent #influenza #vaccines

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.04.28.591370v2

Abstract
With the ever-present threat of pandemics, it is imperative we develop vaccine technologies eliciting broad and durable immunity to high-risk pathogens. Yet, current annual influenza vaccines, for example, fail to provide robust immunity against the 3-4 homologous strains they contain, let alone heterologous strains. Herein, we demonstrate that sustained delivery of multivalent influenza vaccines from an injectable polymer-nanoparticle (PNP) hydrogel technology induces more rapid, consistent, and potent humoral immune responses against multiple homologous viruses, as well as potent responses against heterologous viruses and potential pandemic subtypes H5N1, H7N9 and H9N2. Further, admixing PNP hydrogels with commercial influenza vaccines results in stronger hemagglutination inhibition against both heterologous and homologous viruses. We show this enhanced potency and breadth arises from higher affinity antibodies targeting both the hemagglutinin stem and head. Overall, this simple and effective sustained delivery platform for multivalent annual influenza vaccines generates durable, potent, and remarkably broad immunity to influenza.

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#aH5n1 #aH7n9 #aH9n2 #abstract #avianInfluenza #COVID19 #health #influenza #influenzaA #news #research #vaccine #vaccines

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.11.06.622244v1

Abstract
The current situation with H5N1 highly pathogenic avian influenza virus (HPAI) is causing a worldwide concern due to multiple outbreaks in wild birds, poultry, and mammals. Moreover, multiple zoonotic infections in humans have been reported. Importantly, HPAI H5N1 viruses with genetic markers of adaptation to mammals have been detected. Together with HPAI H5N1, avian influenza viruses H7N9 (high and low pathogenic) stand out due to their high mortality rates in humans. This raises the question of how prepared we are serologically and whether seasonal vaccines are capable of inducing protective immunity against these influenza subtypes. An observational study was conducted in which sera from people born between years 1925-1967, 1968-1977, and 1978-1997 were collected before or after 28 days or 6 months post-vaccination with an inactivated seasonal influenza vaccine. Then, haemagglutination inhibition, viral neutralization, and immunoassays were performed to assess the basal protective immunity of the population as well as the ability of seasonal influenza vaccines to induce protective responses. Our results indicate that subtype-specific serological protection against H5N1 and H7N9 in the representative Spanish population evaluated was limited or nonexistent. However, seasonal vaccination was able to increase the antibody titers to protective levels in a moderate percentage of people, probably due to cross-reactive responses. These findings demonstrate the importance of vaccination and suggest that seasonal influenza vaccines could be used as a first line of defense against an eventual pandemic caused by avian influenza viruses, to be followed immediately by the use of more specific pandemic vaccines.

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https://etidioh.wordpress.com/2024/11/09/are-we-serologically-prepared-against-an-avian-influenza-pandemic-and-could-seasonal-flu-vaccines-help-us/

#aH5n1 #aH7n9 #abstract #avianInfluenza #AVIANINFLUENZA #birdFlu #h5n1 #health #human #news #pandemicInfluenza #research #seasonalInfluenza #serology #vaccination

Source: Veterinary Immunology and Immunopathology, https://www.sciencedirect.com/science/article/abs/pii/S0165242724001375?via%3Dihub

Abstract
The avian influenza A virus (H7N9), first detected in China in 2013, is a zoonotic virus that remains persistent in bird populations despite a decline in human cases owing to control measures. Therefore, this study aimed to develop a vaccine as one preventive strategy in anticipation of the potential entry of H7N9 into Korea. Using the hemagglutinin and neuraminidase consensus sequences of H7N9 from 2018–2019, a recombinant H7N9 vaccine, rgAPQAH7N9, was developed, and its protective efficacy in specific pathogen-free chickens was evaluated. The rgAPQAH7N9 vaccine exhibited proliferation in eggs and demonstrated high immunogenicity, with a hemagglutination inhibition titer of 9.3 log2. Furthermore, the vaccine provided complete protection, as vaccinated chickens did not exhibit clinical signs or viral shedding. Moreover, when the rgAPQAH7N9 vaccine was boosted, the resulting immunity was long-lasting, with hemagglutination inhibition titers > 7 log2 persisting after 6 months. Therefore, the rgAPQAH7N9 vaccine virus may be considered a potential candidate for inclusion in the avian influenza antigen bank to ensure preparedness for emergency vaccination in poultry.

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https://etidioh.wordpress.com/2024/11/03/efficacy-of-the-h7n9-vaccine-as-a-candidate-for-the-korean-avian-influenza-antigen-bank/

#aH7n9 #abstract #avianInfluenza #birdFlu #health #influenza #news #poultry #research #southKorea #vaccination #vaccine

Source: Cell Reports, https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01251-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124724012518%3Fshowall%3Dtrue

Summary
The coronavirus disease 2019 (COVID-19) pandemic has reminded us of human infections with the H7N9 virus and has raised questions related to the clinical and molecular pathophysiological diversity between the two diseases. Here, we performed a proteomic approach on sera samples from patients with H7N9-virus or SARS-CoV-2-virus infection and healthy controls. Compared to SARS-CoV-2, H7N9-virus infection caused elevated neutrophil concentrations, T cell exhaustion, and increased cytokine/interleukin secretion. Cell-type deconvolution and temporal analysis revealed that T cells and neutrophils could regulate the core immunological trajectory and influence the prognosis of patients with severe H7N9-virus infection. Elevated tissue-enhanced proteins combined with alterations of clinical biochemical indexes suggested that H7N9 infection induced more severe inflammatory organ injury and dysfunction in the liver and intestine. Further mechanical analysis revealed that the high concentration of neutrophils might impact the intestinal enterocyte cells through cytokine-receptor interaction, leading to intestinal damage in patients with H7N9-virus infection.

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https://etidioh.wordpress.com/2024/11/03/serum-proteome-reveals-distinctive-molecular-features-of-h7n9-and-sars-cov-2-infected-patients/

#aH7n9 #abstract #AVIANINFLUENZA #covid #COVID19 #health #immunopathology #research #sarsCov2 #vaccine

Source: Viruses, https://www.mdpi.com/1999-4915/16/11/1656

Abstract
Influenza A viruses (IAVs), which belong to the Orthomyxoviridae family, are RNA viruses characterized by a segmented genome that allows them to evolve and adapt rapidly. These viruses are mainly transmitted by wild waterfowl. In this study, we investigated the evolutionary processes of H7Nx (H7N1, H7N2, H7N3, H7N4, H7N5, H7N6, H7N7, H7N8, H7N9) viruses, which pose a significant pandemic risk due to the known cases of human infection and their potential for rapid genetic evolution and reassortment. The complete genome sequences of H7Nx influenza viruses (n = 3239) were compared between each other to investigate their phylogenetic relationships and reassortment patterns. For the selected viruses, phylogenetic trees were constructed for eight genome segments (PB2, PB1, PA, HA, NP, NA, M, NS) to assess the genetic diversity and geographic distribution of these viruses. Distinct phylogenetic clades with remarkable geographic patterns were found for the different segments. While the viruses were consistently grouped by subtype based on the NA segment sequences, the phylogeny of the other segment sequences, with the exception of the NS segment, showed distinct grouping patterns based on geographic origin rather than formal subtype assignment. Reassortment events leading to complex phylogenetic relationships were frequently observed. In addition, multiple cases of previously undescribed reassortments between subtypes were detected, emphasizing the fluidity of H7Nx virus populations. These results indicate a high degree of genetic diversity and reassortment within H7Nx influenza viruses. In other words, H7Nx viruses exist as constantly changing combinations of gene pools rather than stable genetic lineages.

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https://etidioh.wordpress.com/2024/10/23/phylogenetic-insights-into-h7nx-influenza-viruses-uncovering-reassortment-patterns-and-geographic-variability/

#aH7n7 #aH7n9 #abstract #avianInfluenza #reassortantStrain #research

Source: PLoS Pathogens, https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012427

Abstract
The incidence of human infection by zoonotic avian influenza viruses, especially H5N1 and H7N9 viruses, has increased. Current zoonotic H7N9 avian influenza viruses (identified since 2013) emerged during reassortment of viruses belonging to different subtypes. Despite analyses of their genetic background, we do not know why current H7N9 viruses are zoonotic. Therefore, there is a need to identify the factor(s) responsible for the extended host tropism that enables these viruses to infect humans as well as birds. To identify H7N9-specific amino acids that confer zoonotic properties on H7N9 viruses, we performed multiple alignment of the hemagglutinin (HA) amino acid sequences of A/Shanghai/1/2013 (H7N9) and A/duck/Zhejiang/12/2011(H7N3) (a putative, non- or less zoonotic HA donor to the zoonotic H7N9 virus). We also analyze the function of an H7N9 HA-specific amino acid with respect to HA acid stability, and evaluated the effect of acid stability on viral infectivity and virulence in a mouse model. HA2-116D, preserved in current zoonotic H7N9 viruses, was crucial for loss of HA acid stability. The acid-labile HA protein in H7 viruses played an important role in infection of human airway epithelial cells; HA2-116D contributed to infection and replication of H7 viruses. Finally, HA2-116D served as a H7 virulence factor in mice. These results suggest that acid-labile HA harboring HA2-116D confers zoonotic characteristics on H7N9 virus and that future novel zoonotic avian viruses could emerge from non-zoonotic H7 viruses via acquisition of mutations that remove HA acid stability.

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https://etidioh.wordpress.com/2024/10/22/the-host-tropism-of-current-zoonotic-h7n9-viruses-depends-mainly-on-an-acid-labile-hemagglutinin-with-a-single-amino-acid-mutation-in-the-stalk-region/

#aH7n9 #abstract #avianInfluenza #reassortantStrain #research

Source: Lancet Microbe, https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(24)00234-9/fulltext

Summary
A systematic risk assessment approach is essential for evaluating the relative risk of influenza A viruses (IAVs) with pandemic potential. To achieve this, the Tool for Influenza Pandemic Risk Assessment (TIPRA) was developed under the Global Influenza Programme of WHO. Since its release in 2016 and update in 2020, TIPRA has been used to assess the pandemic risk of 11 zoonotic IAVs across ten evaluation rounds. Notably, A(H7N9), A(H9N2), and A(H5) clade 2.3.4.4 viruses were re-evaluated owing to changes in epidemiological characteristics or virus properties. A(H7N9) viruses had the highest relative risk at the time of assessment, highlighting the importance of continuous monitoring and reassessment as changes in epidemiological trends within animal and human populations can alter risk profiles. The knowledge gaps identified throughout the ten risk assessments should help to guide the efficient use of resources for future research, including surveillance. The TIPRA tool reflects the One Health approach and has proven crucial for closely monitoring virus dynamics in both human and non-human populations to enhance preparedness for potential IAV pandemics.

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https://etidioh.wordpress.com/2024/10/14/pandemic-risk-characterisation-of-zoonotic-influenza-a-viruses-using-the-tool-for-influenza-pandemic-risk-assessment-tipra/

#aH5n1 #aH7n9 #aH9n2 #abstract #avianInfluenza #pandemicInfluenza #pandemicPreparedness #research #TIPRA #WHO #zoonoses