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Literature detail

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

Chunyang Gu1 Tadashi Maemura1 Lizheng Guan1 Amie J Eisfeld1 Asim Biswas1 Maki Kiso2 Ryuta Uraki2 Mutsumi Ito2 Sanja Trifkovic1 Tong Wang1 Lavanya Babujee1 Robert Presler1 Randall Dahn1 Yasuo Suzuki3 Peter J Halfmann1 Seiya Yamayoshi2 Gabriele Neumann1 Yoshihiro Kawaoka4,5,6,7
Affiliations 7 institutions
  1. Influenza Research Institute, Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA.
  2. Department of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  3. Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
  4. Influenza Research Institute, Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA. [email protected].
  5. Department of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. [email protected].
  6. The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), University of Tokyo, Tokyo, Japan. [email protected].
  7. The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan. [email protected].
PMID 39467571 2024 Nature eng ppublish
PubMed DOI Browse context

Article

Publication summary

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 workers<sup>1-3</sup>, who presented with mild respiratory symptoms or conjunctivitis, and one individual with no known animal exposure who was hospitalized but recovered<sup>3,4</sup>. Here we characterized A/Texas/37/2024 (huTX37-H5N1), a virus isolated from the eyes of an infected farm worker who developed conjunctivitis<sup>5</sup>. 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.

Disease Models, Animal Ferrets Influenza A Virus, H5N1 Subtype Influenza, Human Orthomyxoviridae Infections Animals Cattle Female Humans Male Mice RNA-Dependent RNA Polymerase Virus Replication

Structured evidence records

Evidence records

6 total
Host Range Experiment 2 records
Host Range Experiment Extraction confidence 0.95
Key finding

The human isolate huTX37-H5N1 replicated efficiently in human cells, caused lethal disease in mice and ferrets, and transmitted by respiratory droplets between ferrets.

Virus
IAV H5N1
Location
Not specified
Supporting text

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.

Method
experimental infection; transmission study; replication assay
Sample type
respiratory organs; non-respiratory organs
Experimental system
in vivo animal experiment
Host Range Experiment Extraction confidence 0.95
Key finding

The huTX37-H5N1 virus replicated efficiently in human alveolar epithelial cells and less efficiently in corneal epithelial cells.

Virus
IAV H5N1
Location
Not specified
Supporting text

huTX37-H5N1 replicated efficiently in primary human alveolar epithelial cells, but less efficiently in corneal epithelial cells.

Method
replication assay
Experimental system
in vitro cell culture
Cross Species Transmission 1 records
Cross Species Transmission Extraction confidence 0.90
Key finding

The bovine-derived H5N1 virus transmitted by respiratory droplets between ferrets, causing lethal infection.

Virus
IAV H5N1
Location
Not specified
Supporting text

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.

Method
experimental infection
Study design
animal experiment
Transmission direction
animal-to-animal
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.80
Key finding

Mutations PB2-631L in bovine H5N1 and PB2-627K in the human isolate huTX37-H5N1 were associated with increased polymerase activity, indicating genomic adaptation to mammalian hosts.

Virus
IAV H5N1
Location
Not specified
Supporting text

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).

Genes or proteins
PB2
Analysis methods
comparative genomic analysis
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.90
Key finding

PB2-631L and PB2-627K mutations in H5N1 enhance polymerase activity in human cells, contributing to mammalian adaptation.

Virus
IAV H5N1
Host
Not specified
Location
Not specified
Supporting text

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).

Genes or proteins
PB2
Mutations
PB2-631L; PB2-627K
Mechanism types
polymerase_activity; mammalian_adaptation
Spillover Event 1 records
Spillover Event Extraction confidence 0.95
Key finding

HPAI H5N1 viruses that infected dairy cattle in the USA caused spillover infections in farm workers, indicating animal-to-human transmission of bovine-derived H5N1.

Virus
IAV H5N1
Location
United States United States
Supporting text

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 workers, who presented with mild respiratory symptoms or conjunctivitis.

Study design
outbreak investigation
Transmission direction
animal-to-human
Geographic raw
USA
Country inferred
United States