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

被引：12

作者：

Sun, Honglei ^{[1
]}

Deng, Guojing ^{[1
]}

Sun, Haoran ^{[1
]}

Song, Jingwei ^{[1
]}

Zhang, Wei ^{[2
]}

Li, Han ^{[1
]}

Wei, Xiaohui ^{[1
]}

Li, Fangtao ^{[1
]}

Zhang, Xin ^{[1
]}

Liu, Jiyu ^{[1
]}

Pu, Juan ^{[1
]}

Sun, Yipeng ^{[1
]}

Tong, Qi ^{[1
]}

Bi, Yuhai ^{[2
]}

Xie, Yufeng ^{[2
,3
]}

Qi, Jianxun ^{[2
]}

Chang, Kin-Chow ^{[4
]}

Gao, George Fu ^{[2
,5
,6
]}

Liu, Jinhua ^{[1
]}

机构：

[1] China Agr Univ, Coll Vet Med, Key Lab Anim Epidemiol & Zoonosis, Minist Agr, Beijing 100193, Peoples R China

[2] Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing 100101, Peoples R China

[3] Tsinghua Univ, Sch Med, Dept Basic Med Sci, Beijing 100084, Peoples R China

[4] Univ Nottingham, Sch Vet Med & Sci, Bonington Campus, Sutton LE12 5RD, Surrey, England

[5] Natl Inst Viral Dis Control & Prevent, Chinese Natl Influenza Ctr, Chinese Ctr Dis Control & Prevent China CDC, Beijing 102206, Peoples R China

[6] WHO Collaborating Ctr Reference & Res Influenza, Beijing 102206, Peoples R China

来源：

PNAS NEXUS | 2022年 / 1卷 / 03期

基金：

中国国家自然科学基金;

关键词：

H5N6 avian influenza virus; hemagglutinin; N-glycosylation; protein stability; mammalian adaptation; RECEPTOR-BINDING SPECIFICITY; A VIRUS; GENETIC-CHARACTERIZATION; TRANSMISSION; H1N1; EVOLUTION; MUTATION;

D O I：

10.1093/pnasnexus/pgac085

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Clade 2.3.4.4 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 2.3.4.4 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.

引用

页数：13

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