Hemagglutinin double-mutation enhances binding of human-infecting avian influenza virus clade 2.3.4.4b H5Ny to human and SLeX receptors
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.
Authors
- George F. Gao (ORCID: https://orcid.org/0000-0002-3869-615X)
- 王海晨 (ORCID: https://orcid.org/0009-0002-2661-1347)
- Z Zhang
- Hao Song (ORCID: https://orcid.org/0000-0002-2811-0370)
- Antonio Di Maio (ORCID: https://orcid.org/0000-0002-2740-9098)
- W H Zhang
- Jianxun Qi (ORCID: https://orcid.org/0000-0002-9358-4732)
- Tianjiao Hao
- Yan Liu (ORCID: https://orcid.org/0000-0002-2566-6867)
- Xi Zhang (ORCID: https://orcid.org/0000-0002-4638-3997)
- Yu Jin (ORCID: https://orcid.org/0000-0002-5429-1080)
- Xiyue Jin
- Lei Sun (ORCID: https://orcid.org/0000-0002-0101-0695)
- Chunge Zhang
- Yuhang Gu
- Yuxuan Wang
- Ningli Wang
- Yuhai Bi
- Pu Han
Institutions
- Beijing Tongren Hospital (CN)
- Capital Medical University (CN)
- Yunnan University (CN)
- Chinese Academy of Sciences (CN)
- Czech Academy of Sciences, Institute of Microbiology (CZ)
- Institute of Microbiology (CN)
- National Institute for Viral Disease Control and Prevention (CN)
- Beijing Ditan Hospital (CN)
- Beijing Center for Disease Prevention and Control (CN)
- Beijing Academy of Science and Technology (CN)
- Hebei University (CN)
- Imperial College London (GB)
Publication Details
- Journal
- EMBO Reports
- Published
- 2026-06-16
- DOI
- https://doi.org/10.1038/s44319-026-00816-2
- Primary Topic
- Influenza Virus Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China