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
Affiliations15 institutions
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].
Beijing Life Science Academy, Beijing 102200, China.
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China
Cryo-EM Center, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, Shanxi, China.
School of Life Sciences, Hebei University, Baoding 071002, Hebei, China.
Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology & Visual Sciences, Beijing 100730, China.
Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
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
National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China. Electronic address: [email protected].
Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology & Visual Sciences, Beijing 100730, China
Henan Academy of Innovations in Medical Science, Zhengzhou 450052, Henan, China. Electronic address: [email protected].
Beijing Life Science Academy, Beijing 102200, China
National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China. Electronic address: [email protected].
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.
Recent outbreaks in cattle highlight concerns about cross-species transmission and zoonotic spillover. The hemagglutinin protein from a cattle-infecting H5N1 virus retained avian-like receptor binding, indicating avian-to-cattle host switch.
HA of cattle-infecting H5N1 shows receptor-binding adaptation, gaining minor affinity for human-type α2-6 receptors while retaining avian α2-3 preference.
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.
HA from a cattle-infecting H5N1 virus binds both α2-6-linked (human-like) and α2-3-linked (avian-like) sialic acid receptors, revealing partial adaptation toward human receptor usage.
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. 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.
Method
cryo-electron microscopy; receptor-binding assay
Receptors
α2-6-linked sialic acid; α2-3-linked sialic acid
Spillover Event1 records
Spillover EventExtraction confidence 0.85
Key finding
A cattle-infecting H5N1 avian influenza virus shows receptor binding and tropism to human tissues, supporting potential animal-to-human spillover.
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. HA also binds effectively to human conjunctival, tracheal, and mammary tissues, indicating a risk for human transmission, notably in cases of conjunctivitis.
