Nature Communications | 2025
16 December 2025
A new study published in Nature Communications sheds light on the molecular mechanisms allowing the H5N1 avian influenza virus to cause widespread outbreaks in dairy cattle. Researchers from the University of Glasgow and international collaborators reveal that the virus's ability to replicate in bovine cells is not a universal trait of H5N1 but is specific to the internal gene constellations of recent 2.3.4.4b clade genotypes.
While much attention is often placed on surface proteins (Hemagglutinin and Neuraminidase) regarding host jumps, this study highlights the critical role of the virus's internal gene cassette (PB2, PB1, PA, NP, M, and NS). The researchers generated over 80 recombinant viruses representing 60 years of H5N1 evolution. They found that the B3.13 genotype, the specific strain currently circulating in US dairy cattle, possesses a distinct replication advantage in bovine skin and udder cells compared to older H5N1 strains.
The study identified specific mutations in the PB2 polymerase subunit, particularly the M631L mutation, as key drivers for this adaptation. This mutation enhances the virus's polymerase activity in mammalian cells. However, the researchers noted that this mutation's effect is context-dependent, requiring a specific genetic background to fully enhance viral fitness. Beyond replication, the bovine-adapted B3.13 virus has evolved superior methods to evade the host's innate immune response. The study demonstrates that these viruses can modulate the bovine interferon (IFN) response more effectively than their avian ancestors. Crucially, the study found that some avian viruses circulating in wild birds already possess internal gene cassettes that replicate efficiently in bovine cells, even before spilling over into cattle. This suggests that the genetic "hardware" required for mammalian infection is already present in the wild bird reservoir, necessitating vigilant genomic surveillance of internal genes, not just surface proteins, to predict future spillover risks.
