A substitution at the cytoplasmic tail of the spike protein enhances SARS-CoV-2 infectivity and immunogenicity

文献类型： 外文期刊

第一作者： Li, Yuhan

作者： Li, Yuhan;Shi, Huicheng;Liu, Yubin;Zhu, Yibin;Cheng, Gong;Zhang, Xianwen;Tai, Wanbo;Mei, Rui;Chen, Xingzhao;Liu, Jianying;Liu, Yang;Cheng, Gong;Liao, Shumin;Huang, Yanhong;Li, Liang;Yu, Xinyang;Yu, Guocan;Zhang, Xianwen;Tian, Mingyao;Wang, Penghua;Yu, Guocan;Cheng, Gong

作者机构：

关键词： SARS-CoV-2; High-frequency mutations; Spike variants; Virus entry; Virus-like particle mRNA vaccine

期刊名称：EBIOMEDICINE （ 影响因子：10.8； 五年影响因子：10.0 ）

ISSN： 2352-3964

年卷期： 2024 年 110 卷

页码：

收录情况： SCI

摘要： Background Global dissemination of SARS-CoV-2 Omicron sublineages has provided a sufficient opportunity for natural selection, thus enabling beneficial mutations to emerge. Characterisation of these mutations uncovers the underlying machinery responsible for the fast transmission of Omicron variants and guides vaccine development for combating the COVID-19 pandemic. Methods Through systematic bioinformatics analysis of 496,606 sequences of Omicron variants, we obtained 40 amino acid substitutions that occurred with high frequency in the S protein. Utilising pseudoviruses and a trans- complementation system of SARS-CoV-2, we identified the effect of high-frequency mutations on viral infectivity and elucidated the molecular mechanisms. Finally, we evaluated the impact of a key emerging mutation on the immune protection induced by the SARS-CoV-2 VLP mRNA vaccine in a murine model. Findings We identified a proline-to-leucine substitution at the 1263rd residue of the Spike protein, and upon investigating the relative frequencies across multiple Omicron sublineages, we found a trend of increasing frequency for P1263L. The substitution significantly enhances the capacity for S-mediated viral entry and improves the immunogenicity of a virus-like particle mRNA vaccine. Mechanistic studies showed that this mutation is located in the FERM binding motif of the cytoplasmic tail and impairs the interaction between the S protein and the Ezrin/Radixin/Moesin proteins. Additionally, this mutation facilitates the incorporation of S proteins into SARS-CoV-2 virions. Interpretation This study offers mechanistic insight into the constantly increasing transmissibility of SARS-CoV-2 Omicron variants and provides a meaningful optimisation strategy for vaccine development against SARS-CoV-2.

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