OmniVira

Receptor binding, structure, and tissue tropism of cattle-infecting H5N1 avian influenza virus hemagglutinin.

Hao Song1 Tianjiao Hao2 Pu Han3,4 Haichen Wang5 Xu Zhang6 Xiaomei Li4 Yuxuan Wang5 Jiamin Chen7 Ying Li8 Xiyue Jin8 Xuefeng Duan8 Wei Zhang8 Yuhai Bi8 Ronghua Jin9,10 Lei Sun11 Ningli Wang12,13 George F Gao14,3,15
Affiliations 15 institutions
  1. National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China. Electronic address: [email protected].
  2. Beijing Life Science Academy, Beijing 102200, China.
  3. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China
  4. Cryo-EM Center, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, Shanxi, China.
  5. School of Life Sciences, Hebei University, Baoding 071002, Hebei, China.
  6. Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology & Visual Sciences, Beijing 100730, China.
  7. Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
  8. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
  9. National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
  10. National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
  11. Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China. Electronic address: [email protected].
  12. Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology & Visual Sciences, Beijing 100730, China
  13. Henan Academy of Innovations in Medical Science, Zhengzhou 450052, Henan, China. Electronic address: [email protected].
  14. Beijing Life Science Academy, Beijing 102200, China
  15. National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China. Electronic address: [email protected].
PMID39848246 DOI10.1016/j.cell.2025.01.019 Year2025 Journal Cell Languageeng Statusppublish

Abstract

The ongoing circulation of highly pathogenic avian influenza (HPAI) A (H5N1) viruses, particularly clade 2.3.4.4b strains, poses a significant threat to animal and public health. Recent outbreaks in cattle highlight concerns about cross-species transmission and zoonotic spillover. Here, we found that the hemagglutinin (HA) protein from a cattle-infecting H5N1 virus has acquired slight binding to human-like α2-6-linked receptors while still exhibiting a strong preference for avian-like α2-3-linked sialic acid receptors. Immunohistochemical staining revealed HA binding to bovine pulmonary and mammary tissues, aligning with clinical observations. HA also binds effectively to human conjunctival, tracheal, and mammary tissues, indicating a risk for human transmission, notably in cases of conjunctivitis. High-resolution cryo-electron microscopy (cryo-EM) structures of this H5 HA in complex with either α2-3 or α2-6 receptors elucidate the molecular mechanisms underlying its receptor-binding properties. These findings provide critical insights into the tropism and transmission potential of this emerging pathogen.

Supporting text Virus Host Location
cattle-infecting influenza virus 1 clade 2.3.4.4b 19 conjunctivitis 1 H5N1 82 host jump 3 human infection 8 mammary gland 2 receptor binding 30 structure 6 tissue tropism 4 Hemagglutinin Glycoproteins, Influenza Virus 180 Influenza A Virus, H5N1 Subtype 300 Receptors, Virus 204 Viral Tropism 45 Animals 1948 Cattle 126 Cryoelectron Microscopy 37 Humans 1440 Lung 65 Orthomyxoviridae Infections 228 Protein Binding 193 Receptors, Cell Surface 28 sialic acid receptor 14

Evidence records

2 total
Experimental Infection
1 records · 1 evidence types
Evidence type Host Range Experiment
1 records
OVE8833 Host Range Experiment
Key finding

Immunohistochemical assays showed that hemagglutinin from a cattle-infecting H5N1 virus bound to bovine and human tissues, indicating cross-species host-range potential.

Virus
Influenza A virus H5N1
Host
domestic cattle Bos taurus Natural host Experimental system human Homo sapiens Experimental system
Location
Not specified
Supporting text

Here, we found that the hemagglutinin (HA) protein from a cattle-infecting H5N1 virus has acquired slight binding to human-like α2-6-linked receptors while still exhibiting a strong preference for avian-like α2-3-linked sialic acid receptors. Immunohistochemical staining revealed HA binding to bovine pulmonary and mammary tissues, aligning with clinical observations. HA also binds effectively to human conjunctival, tracheal, and mammary tissues, indicating a risk for human transmission, notably in cases of conjunctivitis.

Method
immunohistochemistry | tissue binding assay
Sample type
tissues
Experimental system
immunohistochemical staining tissue-binding assay
Functional Mechanism
1 records · 1 evidence types
Evidence type Receptor Usage
1 records
OVE8831 Receptor Usage
Key finding

The hemagglutinin (HA) of a cattle-infecting H5N1 virus binds both α2-3-linked (avian-like) and α2-6-linked (human-like) sialic acid receptors, demonstrating mixed receptor usage.

Virus
Influenza A virus H5N1
Host
domestic cattle Bos taurus Natural host human Homo sapiens Experimental system
Location
Not specified
Supporting text

The hemagglutinin (HA) protein from a cattle-infecting H5N1 virus has acquired slight binding to human-like α2-6-linked receptors while still exhibiting a strong preference for avian-like α2-3-linked sialic acid receptors.

Method
receptor binding assay | cryo-electron microscopy (cryo-EM) | immunohistochemical staining
Receptors
α2-3-linked sialic acid receptor | α2-6-linked sialic acid receptor