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N-linked glycosylation enhances hemagglutinin stability in avian H5N6 influenza virus to promote adaptation in mammals.

Sun, Honglei; Deng, Guojing; Sun, Haoran; Song, Jingwei; Zhang, Wei; Li, Han; Wei, Xiaohui; Li, Fangtao; Zhang, Xin; Liu, Jiyu; Pu, Juan; Sun, Yipeng; Tong, Qi; Bi, Yuhai; Xie, Yufeng; Qi, Jianxun; Chang, Kin-Chow; Gao, George Fu; Liu, Jinhua

N-linked glycosylation enhances hemagglutinin stability in avian H5N6 influenza virus to promote adaptation in mammals. Thumbnail


Honglei Sun

Guojing Deng

Haoran Sun

Jingwei Song

Wei Zhang

Han Li

Xiaohui Wei

Fangtao Li

Xin Zhang

Jiyu Liu

Juan Pu

Yipeng Sun

Qi Tong

Yuhai Bi

Yufeng Xie

Jianxun Qi

Professor of Veterinary Molecular Medicine

George Fu Gao

Jinhua Liu


Clade avian H5Ny viruses, namely H5N2, H5N6, and H5N8, have exhibited unprecedented intercontinental spread in poultry. Among them, only H5N6 viruses are frequently reported to infect mammals and cause serious human infections. In this study, the genetic and biological characteristics of surface hemagglutinin (HA) from clade H5Ny avian influenza viruses (AIVs) were examined for adaptation in mammalian infection. Phylogenetic analysis identified an amino acid (AA) deletion at position 131 of HA as a distinctive feature of H5N6 virus isolated from human patients. This single AA deletion was found to enhance H5N6 virus replication and pathogenicity in vitro and in mammalian hosts (mice and ferrets) through HA protein acid and thermal stabilization that resulted in reduced pH threshold from pH 5.7 to 5.5 for viral-endosomal membrane fusion. Mass spectrometry and crystal structure revealed that the AA deletion in HA at position 131 introduced an N-linked glycosylation site at 129 which increases compactness between HA monomers thus stabilizes the trimeric structure. Our findings provide a molecular understanding of how HA protein stabilization promotes cross-species avian H5N6 virus infection to mammalian hosts.

Journal Article Type Article
Acceptance Date Jun 5, 2022
Online Publication Date Jun 8, 2022
Publication Date 2022-07
Deposit Date Jul 4, 2022
Publicly Available Date Jul 4, 2022
Journal PNAS nexus
Electronic ISSN 2752-6542
Publisher Oxford University Press (OUP)
Peer Reviewed Peer Reviewed
Volume 1
Issue 3
Article Number pgac085
Keywords mammalian adaptation, hemagglutinin, H5N6 avian influenza virus, protein stability, N-glycosylation
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