Polygenic #Determinants of #H5N1 #Adaptation to Bovine Cells

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.11.29.626120v1

Abstract
H5N1 avian influenza virus (lineage 2.3.4.4b, B3.13 genotype) has caused, unexpectedly, a large outbreak in dairy cattle in North America. It is critical to ascertain how this virus has specifically adapted to bovine cells and the molecular determinants of this process. Here, we focused on the contribution of the viral internal genomic segments of H5N1 B3.13 to bovine cells adaptation. We generated 45 reassortant viruses harbouring the haemagglutinin and neuraminidase from A/Puerto Rico/8/1934 and internal gene constellations from several influenza A viruses (IAV) or carrying segment swaps between distinct H5N1 strains. The recombinant B3.13 viruses displayed faster replication kinetics in bovine cells compared to other IAV. Importantly, multiple genomic segments of B3.13 viruses contribute to their faster replicative fitness. Further, recombinants with the B3.13 internal genes were less susceptible than ancestral 2.3.4.4b strain to the bovine IFN response. However, bovine (and human) MX1, a key restriction factor for avian IAV, restricted both ancestral 2.3.4.4b and B3.13 recombinant viruses. Interestingly, the latter escape restriction from human BTN3A3. Finally, recombinant B3.13 was virulent in mice unlike the ancestor 2.3.4.4b recombinant virus. Our results highlight the polygenic nature of influenza host range as multiple internal genes of B3.13 contribute to bovine adaptation.

____

#aH5n1 #abstract #animalModels #avianInfluenza #AVIANINFLUENZA #birdFlu #dairyCow #h5n1 #health #news #research #viralPathogenesis

A 2022 avian #H5N1 #influenza A virus from clade 2.3.4.4b attaches to and replicates better in #human respiratory #epithelium than a 2005 H5N1 virus from clade 2.3.2.1

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.11.27.625596v1?rss=1

Abstract
Background: Highly pathogenic avian influenza (HPAI) H5 viruses of the A/Goose/Guangdong/1/1996 (GsGd) lineage pose significant global risks to wildlife, domestic animals, and humans. Recent cross-species transmission events to mammals, including humans, highlight this risk. Critical determinants for cross-species and intra-species transmission include the ability to attach to and replicate in respiratory epithelial cells. Although these factors have been studied for HPAI H5N1 viruses in the past, limited studies are available for currently circulating strains.

Methods: We compared level of adaptation to human respiratory tract of a HPAI H5N1 clade 2.3.4.4b (H5N1.2022) virus with those of well characterized HPAI H5N1 clade 2.1.3.2 (H5N1.2005) and seasonal H3N2.2003 viruses by three methods. First, we compared pattern of virus attachment by virus histochemistry. Second, we compared efficiency of infection and replication, as well as innate immune responses in human respiratory epithelium in vitro. Lastly, we compared polymerase complex activity in a minigenome assay.

Findings: The H5N1.2022 virus attached more abundantly to and replicated more efficiently in cells of the human respiratory tract compared to H5N1.2005 and H3N2.2003 viruses. This increased replication was not associated with an increased polymerase activity of H5N1.2022 virus compared to H3N2.2003 virus. The efficient replication of H5N1.2022 virus infection induced a robust innate immune response almost comparable to H3N2.2003.

Interpretation: The pattern of virus attachment and replication efficiency of a HPAI H5N1.2022 virus resembled that of H3N2.2003 virus more closely than a HPAI H5N12005. This could contribute to an increased risk for both human infection and virus adaptations to humans.

____

#aH5n1 #abstract #avianInfluenza #AVIANINFLUENZA #birdFlu #h5n1 #health #news #research #viralPathogenesis

#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.

____

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

Source: Nature Communications, https://www.nature.com/articles/s41467-024-53794-1

Abstract
The lack of a permissive cell culture system has limited high-resolution structures of parvovirus B19 (B19V) to virus-like particles (VLPs). In this study, we present the atomic resolution structure (2.2 Å) of authentic B19V purified from a patient blood sample. There are significant differences compared to non-infectious VLPs. Most strikingly, two host protease inhibitors (PIs), inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) and serpinA3, were identified in complex with the capsids in all patient samples tested. The ITIH4 binds specifically to the icosahedral fivefold axis and serpinA3 occupies the twofold axis. The protein-coated virions remain infectious, and the capsid-associated PIs retain activity; however, upon virion interaction with target cells, the PIs dissociate from the capsid prior to viral entry. Our finding of an infectious virion shielded by bound host serum proteins suggests an evolutionarily favored phenomenon to evade immune surveillance and escape host protease activity.

____

https://etidioh.wordpress.com/2024/11/05/infectious-parvovirus-b19-circulates-in-the-blood-coated-with-active-host-protease-inhibitors/

#abstract #biotechnology #health #healthcare #parvovirusB19 #research #viralPathogenesis

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.09.27.615407v1

Abstract
Clade 2.3.4.4b H5N1 high pathogenicity avian influenza virus (HPAIV) has caused a panzootic affecting all continents except Australia, expanding its host range to several mammalian species. In March 2024, H5N1 HPAIV was first detected in dairy cattle and goats in the United States. Since then, over 230 dairy farms across 14 states have tested positive, with zoonotic infections reported among dairy workers. This raises concerns about the virus undergoing evolutionary changes in cattle that could enhance its zoonotic potential. The Influenza glycoprotein haemagglutinin (HA) facilitates entry into host cells through receptor binding and pH-induced fusion with cellular membranes. Adaptive changes in HA modulate virus-host cell interactions. This study compared the HA genes of cattle and goat H5N1 viruses with the dominant avian-origin clade 2.3.4.4b H5N1 in the United Kingdom, focusing on receptor binding, pH fusion, and thermostability. All the tested H5N1 viruses showed binding exclusively to avian-like receptors, with a pH fusion of 5.9, outside the pH range associated with efficient human airborne transmissibility (pH 5.0 to 5.5). We further investigated the impact of emerging HA substitutions seen in the ongoing cattle outbreaks, but saw little phenotypic difference, with continued exclusive binding to avian-like receptor analogues and pHs of fusion above 5.8. This suggests that the HA genes from the cattle and goat outbreaks do not pose an enhanced threat compared to circulating avian viruses. However, given the rapid evolution of H5 viruses, continuous monitoring and updated risk assessments remain essential to understanding virus zoonotic and pandemic risks.

____

https://etidioh.wordpress.com/2024/09/28/the-haemagglutinin-gene-of-bovine-origin-h5n1-influenza-viruses-currently-retains-an-avian-influenza-virus-phenotype/

#aH5n1 #abstract #avianInfluenza #research #viralPathogenesis

Source: Nature, https://www.nature.com/articles/s41586-024-08063-y

Abstract

In March 2024, highly pathogenic avian influenza virus (HPAIV) clade 2.3.4.4b H5N1 infections in dairy cows were first reported from Texas, USA1. Rapid dissemination to more than 190 farms in 13 states followed2. Here, we provide results of two independent clade 2.3.4.4b experimental infection studies evaluating (i) oronasal susceptibility and transmission in calves to a US H5N1 bovine isolate genotype B3.13 (H5N1 B3.13) and (ii) susceptibility of lactating cows following direct mammary gland inoculation of either H5N1 B3.13 or a current EU H5N1 wild bird isolate genotype euDG (H5N1 euDG). Inoculation of the calves resulted in moderate nasal replication and shedding with no severe clinical signs or transmission to sentinel calves. In dairy cows, infection resulted in no nasal shedding, but severe acute mammary gland infection with necrotizing mastitis and high fever was observed for both H5N1 isolates. Milk production was rapidly and drastically reduced and the physical condition of the cows was severely compromised. Virus titers in milk rapidly peaked at 108 TCID50/mL, but systemic infection did not ensue. Notably, adaptive mutation PB2 E627K emerged after intramammary replication of H5N1 euDG. Our data suggest that in addition to H5N1 B3.13, other HPAIV H5N1 strains have the potential to replicate in the udder of cows and that milk and milking procedures, rather than respiratory spread, are likely the primary routes of H5N1 transmission between cattle.

____

https://etidioh.wordpress.com/2024/09/25/h5n1-clade-2-3-4-4b-dynamics-in-experimentally-infected-calves-and-cows/

#aH5n1 #abstract #avianInfluenza #bovine #research #viralPathogenesis