An influenza mutation switch

Abstract

The highly pathogenic influenza H5N1 clade 2.3.4.4b virus has been dominant in birds and bovines in North America since 2021, and was responsible for the first case of human infection by bovine H5N1 in Texas in 2024 (Texas H5). Although this case raised concerns about the adaptation of the virus, there is fortunately a barrier to the interspecies jump as avian-type hemagglutinin (HA) recognizes cell receptors with sialic acid in an α2,3 linkage, whereas human HA recognizes sialic acid in an α2,6 linkage. Therefore, a switch in receptor binding preference is believed to be required for human-to-human transmission. Now, writing in Science, Lin et al. have confirmed the binding switch to the single HA mutation Gln226Leu in Texas H5.

The team started by determining the glycan binding of wild-type bovine Texas H5 HA, the Gln226Leu mutant and other H5 influenza viruses — bearing diverse mutations — using surface plasmon resonance, enzyme-linked immunosorbent assay and glycan array analyses. They found that the introduction of the Gln226Leu mutation switched the binding specificity from avian-type to human-type, though with a weaker binding constant. Other previously identified mutations in the same HA region enhanced the affinity of binding, though were not necessary for binding α2,6 linkages. The researchers next examined the crystal structures of bovine Texas H5 HA with the avian receptor analog LSTa; this was bound similarly to other H5N1 HAs, with Gln226 forming hydrogen bonds with its glycans. Obtaining the crystal structure of the Gln226Leu mutant with the human receptor analog LSTc showed the α2,6 specificity of the protein, with Leu226 making van der Waals contacts with the nonpolar regions of LSTc.