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TitleHemagglutinin double-mutation enhances binding of human-infecting avian influenza virus clade 2.3.4.4b H5Ny to human and SLe receptors.
Journal, issue, pagesEMBO Rep, Year 2026
Publish dateJun 16, 2026
AuthorsXiyue Jin / Pu Han / Yuxuan Wang / Haichen Wang / Chunge Zhang / Antonio Di Maio / Jin Yu / Tianjiao Hao / Yuhang Gu / Zeyu Zhang / Wei Zhang / Jianxun Qi / Yuhai Bi / Xu Zhang / Lei Sun / Ningli Wang / Yan Liu / Hao Song / George F Gao /
PubMed AbstractClade 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 ...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 (SLe) 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.
External linksEMBO Rep / PubMed:42303811
MethodsEM (single particle) / X-ray diffraction
Resolution2.48 - 3.19 Å
Structure data

38008

8x2f

EMDB-38008, PDB-8x2f:
Cryo-EM structure of H5 hemagglutinin from human-infecting H5N8 influenza virus in complex with Sialyl-Lewis X
Method: EM (single particle) / Resolution: 2.62 Å

PDB-8x26:
Crystal structure of H5 hemagglutinin from human-infecting H5N8 influenza virus in complex with LSTa
Method: X-RAY DIFFRACTION / Resolution: 3.12 Å

PDB-8x27:
Crystal structure of H5 hemagglutinin from human-infecting H5N8 influenza virus in complex with LSTc
Method: X-RAY DIFFRACTION / Resolution: 3.04 Å

PDB-8x28:
Crystal structure of H5 hemagglutinin from human-infecting H5N8 influenza virus
Method: X-RAY DIFFRACTION / Resolution: 3.19 Å

PDB-8x29:
Crystal structure of H5 hemagglutinin from swan-infecting H5N8 influenza virus in complex with LSTa
Method: X-RAY DIFFRACTION / Resolution: 2.613 Å

PDB-8x2c:
Crystal structure of H5 hemagglutinin from swan-infecting H5N8 influenza virus
Method: X-RAY DIFFRACTION / Resolution: 2.59 Å

PDB-8x2d:
Crystal structure of H5 hemagglutinin from swan-infecting H5N8 influenza virus complexed with avian receptor analog LSTc
Method: X-RAY DIFFRACTION / Resolution: 2.48 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-GAL:
beta-D-galactopyranose

ChemComp-SIA:
N-acetyl-alpha-neuraminic acid

ChemComp-HOH:
WATER

Source
  • influenza a virus
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / VIRAL PROTEIN-IMMUNE SYSTEM COMPLEX / VIRAL PROTEIN

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