Polymerase mutations underlie early adaptation of H5N1 influenza virus to dairy cattle and other mammals

In 2024, an unprecedented outbreak of H5N1 high pathogenicity avian influenza was detected in dairy cattle in the USA resulting in spillbacks into poultry, wild birds and other mammals including humans. Here, we present molecular and virological evidence that the cattle B3.13 genotype H5N1 viruses rapidly accumulated adaptations in polymerase genes that enabled better replication in bovine cells and tissues, as well as cells of other mammals including humans. We find evidence of several mammalian adaptations in cattle including PB2 M631L, which is found in all cattle sequences, and PA K497R, which is found in the majority. Structurally, PB2 M631L maps to the polymerase-ANP32 interface, an essential host factor…

• DF
  Department for Environment, Food and Rural Affairs, UK Government

  Awards: BB/X006123/1, MR/Y03368X/1
• RS
  Royal Society

  Award: 231225
• IN
  Institut National de la Recherche Agronomique
• DF
  Directorate for Biological Sciences
• MR
  Medical Research Council

  Awards: MR/Y015045/1, MR/Y03368X/1
• BA
  Biotechnology and Biological Sciences Research Council

  Awards: BBS/E/PI/23NB0003, BB/Y007298/1, 23NB0004, BB/V004697/1, BB/V011286/1, BBS/E/PI/23NB0004, BB/X006123/1, BBS/E/RL/230002C, BBS/E/PI/230002B, BBS/E/RL/230002, BBS/E/PI/230002A
• AH
  Animal Health and Veterinary Laboratories Agency

  Award: SE2223