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

• Published in: Science (American Association for the Advancement of Science) Vol. 386; no. 6726; pp. 1128 - 1134
• Main Authors: Lin, Ting-Hui, Zhu, Xueyong, Wang, Shengyang, Zhang, Ding, McBride, Ryan, Yu, Wenli, Babarinde, Simeon, Paulson, James C., Wilson, Ian A.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 06.12.2024
• Subjects: Amino Acid Substitution; Animals; Cattle; Crystallography, X-Ray; Dairy cattle; Genetic analysis; Glutamate receptors; Glutamic acid; Hemagglutinin Glycoproteins, Influenza Virus - chemistry; Hemagglutinin Glycoproteins, Influenza Virus - genetics; Hemagglutinin Glycoproteins, Influenza Virus - metabolism; Hemagglutinins; Humans; Influenza; Influenza A Virus, H5N1 Subtype - genetics; Influenza, Human - virology; Leucine; Marine mammals; Mutation; Orthomyxoviridae Infections - transmission; Orthomyxoviridae Infections - veterinary; Orthomyxoviridae Infections - virology; Pandemics; Receptors; Receptors, Virus - chemistry; Receptors, Virus - genetics; Receptors, Virus - metabolism; Species diversity; Structural analysis; Structural Analysis (Linguistics); Viruses
• DOI: 10.1126/science.adt0180
• ISSN: 0036-8075; 1095-9203

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. In 2021, a highly pathogenic influenza H5N1 clade 2.3.4.4b virus was detected in North America that is capable of infecting a diversity of avian species, marine mammals, and humans. In 2024, clade 2.3.4.4b virus spread widely in dairy cattle in the US, causing a few mild human cases, but retaining specificity for avian receptors. Historically, this virus has caused up to 30% fatality in humans, so Lin et al . performed a genetic and structural analysis of the mutations necessary to fully switch host receptor recognition. A single glutamic acid to leucine mutation at residue 226 of the virus hemagglutinin was sufficient to enact the change from avian to human specificity. In nature, the occurrence of this single mutation could be an indicator of human pandemic risk. —Caroline Ash