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

Nature volume 636, pages 711–718 (2024)Cite this article

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Abstract

The outbreak of clade 2.3.4.4b highly pathogenic avian influenza viruses of the H5N1 subtype (HPAI H5N1) in dairy cattle in the USA has so far resulted in spillover infections of at least 14 farm workers1,2,3, who presented with mild respiratory symptoms or conjunctivitis, and one individual with no known animal exposure who was hospitalized but recovered3,4. Here we characterized A/Texas/37/2024 (huTX37-H5N1), a virus isolated from the eyes of an infected farm worker who developed conjunctivitis5. huTX37-H5N1 replicated efficiently in primary human alveolar epithelial cells, but less efficiently in corneal epithelial cells. Despite causing mild disease in the infected worker, huTX37-H5N1 proved lethal in mice and ferrets and spread systemically, with high titres in both respiratory and non-respiratory organs. Importantly, in four independent experiments in ferrets, huTX37-H5N1 transmitted by respiratory droplets in 17–33% of transmission pairs, and five of six exposed ferrets that became infected died. PB2-631L (encoded by bovine isolates) promoted influenza polymerase activity in human cells, suggesting a role in mammalian adaptation similar to that of PB2-627K (encoded by huTX37-H5N1). In addition, bovine HPAI H5N1 virus was found to be susceptible to polymerase inhibitors both in vitro and in mice. Thus, HPAI H5N1 virus derived from dairy cattle transmits by respiratory droplets in mammals without previous adaptation and causes lethal disease in animal models.

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Fig. 1: Replication in human epithelial cells.
Fig. 2: huTX37-H5N1 is lethal in mice and spreads systemically.
Fig. 3: huTX37-H5N1 is lethal in ferrets and spreads systemically.
Fig. 4: huTX37-H5N1 transmits by respiratory droplets in ferrets.
Fig. 5: Effects of mutations on viral polymerase activity.
Fig. 6: Zanamivir has minimal effects on the outcome of TX001-H5N1 infection in mice.
Fig. 7: Bovine H5N1 is susceptible to polymerase inhibitors.
Fig. 8: Schematic representation of the possible evolution of dairy cow influenza lineages.

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Data availability

Deep-sequencing data have been deposited to the Sequence Read Archive (SRA) under bioproject accession no. PRJNA1163435. SRA accession numbers for individual samples are provided in Supplementary Table 4. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Response (contract no. 75N93021C00014), non-sponsored discretionary funding and by grants from the Japan Agency for Medical Research and Development (nos. JP24wm0125002, JP243fa627001 and JP24fk0108626 to Y.K.). We thank H. D. Nguyen and P. Jester for technical assistance, and S. Watson for editing the manuscript. The illustrations used in Fig. 8 were created with BioRender (https://biorender.com)7.

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Author notes

  1. These authors contributed equally: Chunyang Gu, Tadashi Maemura, Lizheng Guan, Amie J. Eisfeld, Asim Biswas, Maki Kiso

Authors and Affiliations

  1. Influenza Research Institute, Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA

    Chunyang Gu, Tadashi Maemura, Lizheng Guan, Amie J. Eisfeld, Asim Biswas, Sanja Trifkovic, Tong Wang, Lavanya Babujee, Robert Presler Jr, Randall Dahn, Peter J. Halfmann, Gabriele Neumann & Yoshihiro Kawaoka

  2. Department of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Maki Kiso, Ryuta Uraki, Mutsumi Ito, Seiya Yamayoshi & Yoshihiro Kawaoka

  3. Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

    Yasuo Suzuki

  4. The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), University of Tokyo, Tokyo, Japan

    Yoshihiro Kawaoka

  5. The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan

    Yoshihiro Kawaoka

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  1. Chunyang Gu
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Contributions

Author contributions are provided according to Contributor Roles Taxonomy (CRediT). Conceptualization: A.J.E., P.J.H., G.N. and Y.K. Data curation: C.G., T.M., L.G., A.J.E., A.B., M.K. and R.U. Formal analysis: A.J.E., M.K., R.U., L.B. and S.Y. Funding acquisition: Y.K. Investigation: C.G., T.M., L.G., A.J.E., A.B., M.K., R.U., M.I., T.W., L.B., R.P., R.D. and S.Y. Methodology: C.G., T.M., L.G., A.J.E., A.B., M.K., R.U., M.I., L.B., R.D., P.J.H., S.Y., G.N. and Y.K. Project administration: A.J.E., P.J.H., S.T. and G.N. Resources: Y.S. and Y.K. Software: L.B. and R.P. Supervision: Y.K. Validation: C.G., T.M., L.G., A.J.E., A.B., M.K., R.U., T.W., L.B. and R.D. Visualization: A.J.E., M.K. and R.U. Writing—original draft: A.J.E., G.N. and Y.K. Writing—review and editing: C.G., T.M., L.G., A.J.E., A.B., M.K., R.U., M.I., S.T., T.W., L.B., R.P., R.D., Y.S., P.J.H., S.Y., G.N. and Y.K. Author contributions to specific experiments: ALI epithelial cell infection experiments were performed by T.M., L.G., A.J.E., A.B. and T.W. Mouse pathogenicity experiments were performed by C.G., L.G., A.J.E., A.B. and T.W. Ferret pathogenicity and transmission experiments were performed by C.G., T.M., L.G., A.J.E., A.B. and T.W. Minireplicon assays were performed by T.M. Receptor-binding studies were performed by T.M. Antiviral susceptibility testing experiments were performed by M.K., R.U., M.I. and S.Y. Sequence and deep-sequencing analysis was performed by L.B., R.P., R.D. and G.N.

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Correspondence to Yoshihiro Kawaoka.

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Extended data figures and tables

Extended Data Fig. 1 Clinical data and virus titres associated with ferrets used to assess respiratory droplet transmission.

For infected ferrets (donors) shown in Fig. 4 (N = 6 biologically independent animals per dose), daily body weights (A), body temperatures (B), and survival (C) are given. In panels (A) and (B), data points represent mean values and error bars represent the standard deviation. Survival curves in panel (C) were compared by using a log-rank Mantel-Cox test and the p-value is reported in the figure panel. Panel (D) shows virus titres in tissues of the same animals collected at the time of euthanasia or within 14 h of death. Each dot represents the titre of an individual ferret. °C, degrees Celsius; d, days; PFU, plaque forming units; PFU/g, plaque forming units per gram of tissue; PFU/ml, plaque forming units per millilitre.

Source Data

Extended Data Fig. 2 huTX37-H5N1 receptor binding activity.

Four-fold serial dilutions of α2,3 and α2,6 sialylglycopolymers adhered to microtitre plates were incubated with 32 hemagglutination (HA) units of the indicated viruses or PBS (negative control). After washing, virus binding was detected by an anti-HA human monoclonal antibody (CR9114) and an HRP-conjugated secondary antibody. The absorbance values for each condition with each virus or PBS are shown. Each dot represents a single biologically independent replicate value. Three independent replicate experiments are shown.

Source Data

Extended Data Table 1 Amino acid differences among the cow HPAI H5N1 viruses used in this study
Full size table
Extended Data Table 2 Comparison of tissue titres in huTX37-H5N1- and NM93-H5N1-infected BALB/cJ mice
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Extended Data Table 3 Comparison of tissue titres in huTX37-H5N1- and NM93-H5N1-infected ferrets
Full size table
Extended Data Table 4 In vitro inhibitory activity of neuraminidase inhibitors
Full size table
Extended Data Table 5 In vitro inhibitory activity of polymerase inhibitors
Full size table

Supplementary information

Reporting Summary

Supplementary Table 1

Non-synonymous mutations detected in inocula used to infect ferrets and the nasal swabs of infected and exposed ferrets in respiratory droplet transmission experiments. Shown are mutations that resulted in amino acid changes in at least 3% of sequence reads.

Supplementary Table 2

Amino acid consensus sequences of virus inoculum, and of viruses isolated from nasal swabs of infected and exposed animals.

Supplementary Table 3

Forward and reverse primers used in deep sequencing for each genome segment.

Supplementary Table 4

SRA accession numbers for deep-sequencing data associated with inocula used to infect ferrets and ferret nasal swab samples.

Source data

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Gu, C., Maemura, T., Guan, L. et al. A human isolate of bovine H5N1 is transmissible and lethal in animal models. Nature 636, 711–718 (2024). https://doi.org/10.1038/s41586-024-08254-7

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