A single nonsynonymous mutation on ZIKV E protein-coding sequences leads to markedly increased neurovirulence in vivo

作     者：Zhihua Liu Yawei Zhang Mengli Cheng Ningning Ge Jiayi Shu Zhiheng Xu Xiao Su Zhihua Kou Yigang Tong Chengfeng Qin Xia Jin Zhihua Liu;Yawei Zhang;Mengli Cheng;Ningning Ge;Jiayi Shu;Zhiheng Xu;Xiao Su;Zhihua Kou;Yigang Tong;Chengfeng Qin;Xia Jin

作者机构：Institut Pasteur of ShanghaiChinese Academy of SciencesShanghai200031China University of Chinese Academy of SciencesBeijing100049China Vaccine and Immunology Research CenterTranslational Medical Research InstituteShanghai Public Health Clinical CenterFudan UniversityShanghai201508China State Key Laboratory of Pathogen and BiosecurityBeijing Institute of Microbiology and EpidemiologyBeijing100071China State Key Laboratory of Molecular Developmental BiologyCAS Center for Excellence in Brain Science and Intelligence TechnologyInstitute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing100101China College of Life Science and TechnologyBeijing University of Chemical TechnologyBeijing100029China 

出 版 物：《Virologica Sinica》 (中国病毒学（英文版）)

年 卷 期：2022年第37卷第1期

页      面：115-126页

核心收录：

学科分类：0710[理学-生物学] 1001[医学-基础医学(可授医学、理学学位)] 100103[医学-病原生物学] 10[医学] 

基　　金：supported in part by the following grants:Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29040301 to X.J.) National Key R&D Program of China(2016YFC1201000 to X.J.) Ministry of Science and Technology of China(2016YFE0133500 to X.J.) the National Natural Science Foundation of China(31770190 and 81925025 to CF.Q.) European Union Horizon 2020 Research and Innovation Programme under ZIKAlliance Grant Agreement(734548 to X.J.) 

主　　题：Zika virus(ZIKV) Envelope protein D67N Mutation Neurovirulence 

摘      要：Zika virus(ZIKV)can infect a wide range of tissues including the developmental brain of human fetus.Whether specific viral genetic variants are linked to neuropathology is incompletely understood.To address this,we have intracranially serially passaged a clinical ZIKV isolate(SW01)in neonatal mice and discovered variants that exhibit markedly increased virulence and neurotropism.Deep sequencing analysis combining with molecular virology studies revealed that a single 67D(Aspartic acid)to N(Asparagine)substitution on E protein is sufficient to confer the increased virulence and neurotropism in vivo.Notably,virus clones with D67N mutation had higher viral production and caused more severe cytopathic effect(CPE)in human neural astrocytes U251 cells in vitro,indicating its potential neurological toxicity to human brain.These findings revealed that a single mutation D67N on ZIKV envelope may lead to severe neuro lesion that may help to explain the neurovirulence of ZIKV and suggest monitoring the occurrence of this mutation during nature infection may be important.