A single amino acid substitution in the capsid protein of Zika virus contributes to a neurovirulent phenotype

Guang-Yuan Song, Xing-Yao Huang, Meng-Jiao He, Hang-Yu Zhou, Rui-Ting Li, Ying Tian, Yan Wang, Meng-Li Cheng, Xiang Chen, Rong-Rong Zhang, Chao Zhou, Jia Zhou, Xian-Yang Fang, Xiao-Feng Li () and Cheng-Feng Qin ()
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Guang-Yuan Song: Anhui Medical University
Xing-Yao Huang: Academy of Military Medical Sciences
Meng-Jiao He: Academy of Military Medical Sciences
Hang-Yu Zhou: Chinese Academy of Medical Sciences & Peking Union Medical College
Rui-Ting Li: Academy of Military Medical Sciences
Ying Tian: Anhui Medical University
Yan Wang: Tsinghua University
Meng-Li Cheng: Academy of Military Medical Sciences
Xiang Chen: Academy of Military Medical Sciences
Rong-Rong Zhang: Academy of Military Medical Sciences
Chao Zhou: Academy of Military Medical Sciences
Jia Zhou: Academy of Military Medical Sciences
Xian-Yang Fang: Chinese Academy of Sciences
Xiao-Feng Li: Academy of Military Medical Sciences
Cheng-Feng Qin: Anhui Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Increasing evidence shows the African lineage Zika virus (ZIKV) displays a more severe neurovirulence compared to the Asian ZIKV. However, viral determinants and the underlying mechanisms of enhanced virulence phenotype remain largely unknown. Herein, we identify a panel of amino acid substitutions that are unique to the African lineage of ZIKVs compared to the Asian lineage by phylogenetic analysis and sequence alignment. We then utilize reverse genetic technology to generate recombinant ZIKVs incorporating these lineage-specific substitutions based on an infectious cDNA clone of Asian ZIKV. Through in vitro characterization, we discover a mutant virus with a lysine to arginine substitution at position 101 of capsid (C) protein (termed K101R) displays a larger plaque phenotype, and replicates more efficiently in various cell lines. Moreover, K101R replicates more efficiently in mouse brains and induces stronger inflammatory responses than the wild type (WT) virus in neonatal mice. Finally, a combined analysis reveals the K101R substitution promotes the production of mature C protein without affecting its binding to viral RNA. Our study identifies the role of K101R substitution in the C protein in contributing to the enhanced virulent phenotype of the African lineage ZIKV, which expands our understanding of the complexity of ZIKV proteins.

Date: 2023
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DOI: 10.1038/s41467-023-42676-7

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