A human isolate of bovine H5N1 is transmissible and lethal in animal models

Gu, Chunyang; Maemura, Tadashi; Guan, Lizheng; Eisfeld, Amie J.; Biswas, Asim; Kiso, Maki; Uraki, Ryuta; Ito, Mutsumi; Trifkovic, Sanja; Wang, Tong; Babujee, Lavanya; Presler, Robert; Dahn, Randall; Suzuki, Yasuo; Halfmann, Peter J.; Yamayoshi, Seiya; Neumann, Gabriele; Kawaoka, Yoshihiro

doi:10.1038/s41586-024-08254-7

Cited by 4 publications

References 46 publications

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Influenza A(H5N1) shedding in air corresponds to transmissibility in mammals

Tosheva,

Filaire,

Rijnink

et al. 2024

Nat Microbiol

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An increase in spillover events of highly pathogenic avian influenza A(H5N1) viruses to mammals suggests selection of viruses that transmit well in mammals. Here we use air-sampling devices to continuously sample infectious influenza viruses expelled by experimentally infected ferrets. The resulting quantitative virus shedding kinetics data resembled ferret-to-ferret transmission studies and indicated that the absence of transmission observed for earlier A(H5N1) viruses was due to a lack of infectious virus shedding in the air, rather than the absence of necessary mammalian adaptation mutations. Whereas infectious human A(H1N1pdm) virus was efficiently shed in the air, infectious 2005 zoonotic and 2024 bovine A(H5N1) viruses were not detected in the air. By contrast, shedding of infectious virus was observed for 1 out of 4 ferrets infected with a 2022 European polecat A(H5N1) virus and a 2024 A(H5N1) virus isolated from a dairy farm worker.

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Influenza A(H5N1) shedding in air corresponds to transmissibility in mammals

Tosheva,

Filaire,

Rijnink

et al. 2024

Nat Microbiol

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Structural Convergence and Water-Mediated Substrate Mimicry Enable Broad Neuraminidase Inhibition by Human Antibodies

Lederhofer,

Borst,

Nguyen

et al. 2024

Preprint

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Influenza has been responsible for multiple global pandemics and seasonal epidemics and claimed millions of lives. The imminent threat of a panzootic outbreak of avian influenza H5N1 virus underscores the urgent need for pandemic preparedness and effective countermeasures, including monoclonal antibodies (mAbs). Here, we characterize human mAbs that target the highly conserved catalytic site of viral neuraminidase (NA), termed NCS mAbs, and the molecular basis of their broad specificity. Cross-reactive NA-specific B cells were isolated by using stabilized NA probes of non-circulating subtypes. We found that NCS mAbs recognized multiple NAs of influenza A as well as influenza B NAs and conferred prophylactic protections in mice against H1N1, H5N1, and influenza B viruses. Cryo-electron microscopy structures of two NCS mAbs revealed that they rely on structural mimicry of sialic acid, the substrate of NA, by coordinating not only amino acid side chains but also water molecules, enabling inhibition of NA activity across multiple influenza A and B viruses, including avian influenza H5N1 clade 2.3.4.4b viruses. Our results provide a molecular basis for the broad reactivity and inhibitory activity of NCS mAbs targeting the catalytic site of NA through substrate mimicry.

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Polygenic Determinants of H5n1 Adaptation to Bovine Cells

Turnbull,

Zakaria,

Upfold

et al. 2024

Preprint

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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.

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A human isolate of bovine H5N1 is transmissible and lethal in animal models

Cited by 4 publications

References 46 publications

Influenza A(H5N1) shedding in air corresponds to transmissibility in mammals

Influenza A(H5N1) shedding in air corresponds to transmissibility in mammals

Structural Convergence and Water-Mediated Substrate Mimicry Enable Broad Neuraminidase Inhibition by Human Antibodies

Polygenic Determinants of H5n1 Adaptation to Bovine Cells

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