OmniVira

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

Xiyue Jin1,2 Pu Han1 Yuxuan Wang3 Haichen Wang3,4 Chunge Zhang1,5 Antonio Di Maio6 Jin Yu6 Tianjiao Hao7 Yuhang Gu1,8 Zeyu Zhang7 Wei Zhang1 Jianxun Qi1 Yuhai Bi1,5 Xu Zhang9 Lei Sun10 Ningli Wang9 Yan Liu11 Hao Song12 George F Gao13,14
Affiliations 14 institutions
  1. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  2. Beijing Key Laboratory of Surveillance, Early Warning and Pathogen Research on Emerging Infectious Diseases, Beijing Center for Disease Prevention and Control, Beijing, China.
  3. School of Life Sciences, Hebei University, Baoding, Hebei, China.
  4. National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Key Laboratory of Viral Infectious Diseases, Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
  5. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing, China.
  6. Glycosciences Laboratory, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK.
  7. Beijing Life Science Academy, Beijing, China.
  8. School of Life Sciences, Yunnan University, Kunming, China.
  9. Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology & Visual Sciences, Beijing, China.
  10. Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
  11. Glycosciences Laboratory, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK. [email protected].
  12. National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Key Laboratory of Viral Infectious Diseases, Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China. [email protected].
  13. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. [email protected].
  14. National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. [email protected].
PMID42303811 DOI10.1038/s44319-026-00816-2 Year2026 Journal EMBO reports EMBO Rep Languageeng Publication statusActive
Active Last checked 2026-09-29 03:30:36 Source: NCBI PubMed

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 LewisX (SLeX) 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.

Supporting text Virus Host Location
Hemagglutinin Glycoproteins, Influenza Virus 183 Influenza A virus 191 Influenza, Human 290 Mutation 211 Oligosaccharides 3 Receptors, Virus 208 Animals 1981 Ducks 86 Humans 1455 Influenza in Birds 352 Protein Binding 194 Virus Attachment 55

Evidence records

3 total
Functional Mechanism
2 records · 2 evidence types
Evidence type Receptor Usage
1 records
OVE11834 Receptor Usage
Key finding

HA mutations K222Q and S227R in a human-infecting H5N8 strain increase binding to α2-6-linked glycans and Sialyl Lewis X (SLeX) receptors, expanding receptor specificity.

Virus
human-infecting H5N8 strain clade 2.3.4.4b H5Ny highly pathogenic avian influenza viruses
Host
human Homo sapiens Experimental system duck trachea Experimental system
Location
Not specified
Supporting text

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 LewisX (SLeX) glycans

Method
glycan binding assay | structural analyses
Receptors
α2-6-linked glycans | Sialyl LewisX (SLeX) glycans
Evidence type Molecular Adaptation
1 records
OVE11835 Molecular Adaptation
Key finding

HA double mutation K222Q+S227R in a human-infecting clade 2.3.4.4b H5N8 enhances binding to α2-6-linked and Sialyl Lewis X glycans, expanding receptor specificity linked to cross-species potential.

Virus
human-infecting H5N8 strain clade 2.3.4.4b H5Ny highly pathogenic avian influenza viruses
Host
Not specified
Location
Not specified
Supporting text

two naturally occurring mutations (K222Q and S227R) in the hemagglutinin (HA) of a human-infecting H5N8 strain ... enhance binding affinity for both α2-6-linked and Sialyl LewisX (SLeX) glycans... 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.

Genes or proteins
hemagglutinin | HA
Receptors
α2-6-linked glycans | Sialyl LewisX (SLeX)
Mutations
K222Q | S227R
Mechanism types
receptor binding | receptor usage | host-range expansion | tissue tropism
Genomic Evolution
1 records · 1 evidence types
Evidence type Phylogenetic Evolution
1 records
OVE11836 Phylogenetic Evolution
Key finding

Clade 2.3.4.4b H5Ny viruses had evolved dual receptor specificity by the 2020 Russian H5N8 strain.

Virus
clade 2.3.4.4b H5Ny viruses 2020 Russian H5N8 strain
Host
Not specified
Location
Not specified
Supporting text

Our findings suggest that clade 2.3.4.4b H5Ny viruses evolved dual receptor specificity as early as the 2020 Russian H5N8 strain

Genes or proteins
hemagglutinin (HA)
Analysis methods
evolutionary inference based on temporal lineage context | comparative genomic/structural analysis