Avian influenza viruses can cross species barriers, occasionally infecting mammals and humans. In 2021, a highly pathogenic H5N1 clade 2.3.4.4b virus was identified in North America, infecting various bird species, marine mammals and humans. By 2024, this virus was detected in dairy cattle in the United States, with confirmed human cases of bovine H5N1 that involved close contact with infected cattle. A major barrier to the transmission of avian influenza viruses to humans is the mismatch in receptor specificity of the viral haemagglutinin (HA) envelope protein, which binds host sialic acid receptors. In a recent study, Lin et al. uncovered that a single substitution in bovine influenza H5N1 HA switches the specificity to human receptors.

The authors analysed the HA protein from a bovine H5N1 virus isolated from a dairy farm worker (A/Texas/37/2024) and found that it retained a preference for avian-type receptors. Remarkably, a single glutamine-to-leucine substitution at position 226 (Gln226Leu) of the viral HA switched the binding specificity to human-type receptors, and this effect was enhanced by an additional asparagine-to-lysine substitution at position 224. Crystal structures of A/Texas/37/2024 H5N1 virus HA with an avian receptor analogue and the Gln226Leu mutant with a human receptor analogue, revealed the structural basis for this shift.