In 2024, scientists detected an outbreak of highly pathogenic H5N1 avian influenza in dairy cattle in the United States. The virus spread among cattle and also spilled back into poultry, wild birds, other mammals, and humans.
Writing in Nature Communications, researchers from The Pirbright Institute and six collaborating organisations describe how the virus rapidly adapted to cattle and gained an enhanced ability to replicate in mammalian cells, including human cells.
The team studied the B3.13 genotype of H5N1 circulating in US dairy herds and found that, after jumping from birds into mammals, the virus quickly accumulated specific mutations in its polymerase genes, which are essential for viral replication. One mutation, PB2 M631L, was present in all cattle virus sequences analysed, while another, PA K497R, appeared in the vast majority.
Through genetic, structural, and functional analyses, the researchers showed that the PB2 M631L mutation improves interactions between the viral polymerase and a critical host protein called ANP32, particularly the bovine version ANP32A. This interaction is required for efficient replication of the viral genome. Viruses carrying this mutation replicated more effectively in bovine mammary tissue, bovine respiratory cells, and primary human airway cultures.
The study also found evidence of continued viral evolution within cattle. Additional polymerase mutations, including the mammalian adaptation PB2 E627K and the repeatedly emerging PB2 D740N change, further increased viral replication in a range of mammalian cells, with little or no negative impact on replication in birds.
“Our results show the circulation of H5N1 in dairy cattle is actively driving viral adaptation to mammals,” said Dr Thomas Peacock, co-corresponding author and Fellow at The Pirbright Institute. “This improves the virus’s ability to replicate in cattle and heightens the risk of zoonotic spillover.”
“Infections in humans linked to the cattle outbreak have so far been mild and limited, but the findings are concerning,” Dr Peacock added. “The adapted cattle virus replicates efficiently in human cells, retains the ability to infect birds and swine, and shows no clear fitness cost that would prevent it from spreading between species. While current evidence suggests it does not yet transmit efficiently between humans, continued exposure and viral evolution increase the risk of further adaptations that could change this.”
The researchers emphasise the need for continued surveillance of influenza viruses in cattle and other animals, particularly monitoring polymerase gene changes that indicate adaptation to mammals. They also call for the urgent development of broadly protective H5 influenza vaccines for both animals and humans.
The study involved researchers from the Royal Veterinary College, Imperial College, the Roslin Institute, Great Ormond Street UCL Institute of Child Health, the MRC University of Glasgow Centre for Virus Research, and the University of Oxford.
For further information about Pirbright’s work investigating how influenza viruses adapt across species, visit the Zoonotic Influenza Viruses webpage.