Characterization of Two Heterogeneous Lethal Mouse-Adapted SARS-CoV-2 Variants Recapitulating Representative Aspects of Human COVID-19

文献类型： 外文期刊

第一作者： Yan, Feihu

作者： Yan, Feihu;Li, Entao;Wang, Tiecheng;Li, Yuanguo;Liu, Jun;Wang, Weiqi;Qin, Tian;Su, Rina;Pei, Hongyan;Wang, Shen;Feng, Na;Zhao, Yongkun;Yang, Songtao;Xia, Xianzhu;Gao, Yuwei;Li, Yuanguo;Wang, Weiqi;Qin, Tian;Su, Rina;Pei, Hongyan;Gao, Yuwei

作者机构：

关键词： COVID-19; SARS-CoV-2; mouse model; mutation; pathogenesis; BLP vaccine

期刊名称：FRONTIERS IN IMMUNOLOGY （ 影响因子：8.786； 五年影响因子：8.876 ）

ISSN： 1664-3224

年卷期： 2022 年 13 卷

页码：

收录情况： SCI

摘要： New emerging severe acute respiratory syndrome 2 (SARS-CoV-2) has caused a worldwide pandemic. Several animal models of coronavirus disease 2019 (COVID-19) have been developed and applied to antiviral research. In this study, two lethal mouse-adapted SARS-CoV-2 variants (BMA8 and C57MA14) with different virulence were generated from different hosts, which are characterized by high viral replication titers in the upper and lower respiratory tract, pulmonary pathology, cytokine storm, cellular tropism, lymphopenia, and neutrophilia. Two variants exhibit host genetics-related and age-dependent morbidity and mortality in mice, exquisitely reflecting the clinical manifestation of asymptomatic, moderate, and severe COVID-19 patients. Notably, both variants equally weaken the neutralization capacity of the serum derived from COVID-19 convalescent, but the C57MA14 variant showed a much higher virulence than the BMA8 variant in vitro. Q489H substitution in the receptor-binding domain (RBD) of BMA8 and C57MA14 variants results in the receptors of SARS-CoV-2 switching from human angiotensin-converting enzyme 2 (hACE2) to murine angiotensin-converting enzyme 2 (mACE2). Additionally, A22D and A36V mutation in E protein were first reported in our study, which potentially contributed to the virulence difference between the two variants. Of note, the protective efficacy of the novel bacterium-like particle (BLP) vaccine candidate was validated using the BMA8- or C57MA14-infected aged mouse model. The BMA8 variant- and C57MA14 variant-infected models provide a relatively inexpensive and accessible evaluation platform for assessing the efficacy of vaccines and novel therapeutic approaches. This will promote further research in the transmissibility and pathogenicity mechanisms of SARS-CoV-2.

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