A single mutation in bovine influenza H5N1 hemagglutinin switches specificity to human receptors

In 2024, several human infections with highly pathogenic clade 2.3.4.4b bovine influenza H5N1 viruses in the United States raised concerns about their capability for bovine-to-human or even human-to-human transmission. In this study, analysis of the hemagglutinin (HA) from the first-reported human-infecting bovine H5N1 virus (A/Texas/37/2024, Texas) revealed avian-type receptor binding preference. Notably, a Gln ²²⁶ Leu substitution switched Texas HA binding specificity to human-type receptors, which was enhanced when combined with an Asn ²²⁴ Lys mutation. Crystal structures of the Texas HA with avian receptor analog LSTa and its Gln ²²⁶ Leu mutant with human receptor analog LSTc elucidated the structural basis for this preferential receptor recognition. These findings highlight the need for continuous surveillance of emerging mutations in avian and bovine clade 2.3.4.4b H5N1 viruses.