What does this research mean for the field?

Two naturally occurring mutations (K222Q and S227R) in the hemagglutinin of clade 2.3.4.4b H5Ny avian influenza viruses enhance binding affinity for human and SLeX receptors, enabling dual receptor specificity and facilitating cross-species transmission. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research investigates how mutations in avian influenza hemagglutinin enhance receptor binding to facilitate cross-species transmission.

June 18, 2026Open Access

Hemagglutinin double-mutation enhances binding of human-infecting avian influenza virus clade 2.3.4.4b H5Ny to human and SLeX receptors

Key Points

This research investigates how mutations in avian influenza hemagglutinin enhance receptor binding to facilitate cross-species transmission.
Analyzed mutations K222Q and S227R in H5Ny hemagglutinin from a 2020 human-infecting strain.
Conducted structural analyses to assess binding affinity for α2-6-linked and SLeX glycans.
The mutations increased binding affinity to α2-6-linked and SLeX glycans, relevant in both human and bird tissues.
Expanded receptor specificity was confirmed through structural analyses, suggesting potential for cross-species transmission.

Abstract

Abstract Clade 2.3.4.4b H5Ny highly pathogenic avian influenza viruses (HPAIVs) continue to circulate worldwide, posing zoonotic threats, especially with recent cattle outbreaks. The mechanisms by which these viruses adapt to mammalian hosts while maintaining a broad avian tropism remain poorly understood. Here, we demonstrate that two naturally occurring mutations (K222Q and S227R) in the hemagglutinin (HA) of a human-infecting H5N8 strain, first identified in 2020, enhance binding affinity for both α2-6-linked and Sialyl Lewis X (SLe X ) glycans, which may underlie the broad tissue binding and cross-species potential. Structural analyses reveal that these mutations expand receptor specificity for these glycans, which are abundant in the human respiratory tract and duck trachea, providing a possible molecular basis for cross-species transmission. Our findings suggest that clade 2.3.4.4b H5Ny viruses evolved dual receptor specificity as early as the 2020 Russian H5N8 strain, potentially contributing to sporadic human infections and widespread dissemination among birds and mammals.

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