PMID- 35197985 OWN - NLM STAT- MEDLINE DCOM- 20220301 LR - 20220301 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - Characterization of Two Heterogeneous Lethal Mouse-Adapted SARS-CoV-2 Variants Recapitulating Representative Aspects of Human COVID-19. PG - 821664 LID - 10.3389/fimmu.2022.821664 [doi] LID - 821664 AB - 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. CI - Copyright (c) 2022 Yan, Li, Wang, Li, Liu, Wang, Qin, Su, Pei, Wang, Feng, Zhao, Yang, Xia and Gao. FAU - Yan, Feihu AU - Yan F AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. FAU - Li, Entao AU - Li E AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. FAU - Wang, Tiecheng AU - Wang T AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. FAU - Li, Yuanguo AU - Li Y AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. AD - College of Veterinary Medicine, Jilin University, Changchun, China. FAU - Liu, Jun AU - Liu J AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. FAU - Wang, Weiqi AU - Wang W AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. AD - College of Veterinary Medicine, Jilin University, Changchun, China. FAU - Qin, Tian AU - Qin T AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. AD - School of Life Sciences, Northeast Normal University, Changchun, China. FAU - Su, Rina AU - Su R AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. AD - College of Veterinary Medicine, Jilin Agricultural University, Changchun, China. FAU - Pei, Hongyan AU - Pei H AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. AD - College of Veterinary Medicine, Jilin Agricultural University, Changchun, China. FAU - Wang, Shen AU - Wang S AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. FAU - Feng, Na AU - Feng N AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. FAU - Zhao, Yongkun AU - Zhao Y AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. FAU - Yang, Songtao AU - Yang S AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. FAU - Xia, Xianzhu AU - Xia X AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. FAU - Gao, Yuwei AU - Gao Y AD - Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. AD - College of Veterinary Medicine, Jilin Agricultural University, Changchun, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220207 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Spike Glycoprotein, Coronavirus) RN - 0 (spike protein, SARS-CoV-2) RN - EC 3.4.17.23 (ACE2 protein, human) RN - EC 3.4.17.23 (Ace2 protein, mouse) RN - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2) RN - SARS-CoV-2 variants SB - IM MH - Amino Acid Substitution MH - Angiotensin-Converting Enzyme 2/genetics/immunology MH - Animals MH - *COVID-19/genetics/immunology MH - Disease Models, Animal MH - Female MH - Humans MH - Mice MH - Mice, Inbred BALB C MH - Mice, Knockout MH - *Mutation, Missense MH - *SARS-CoV-2/genetics/immunology MH - Spike Glycoprotein, Coronavirus/genetics/immunology PMC - PMC8858946 OTO - NOTNLM OT - BLP vaccine OT - COVID-19 OT - SARS-CoV-2 OT - mouse model OT - mutation OT - pathogenesis COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/02/25 06:00 MHDA- 2022/03/03 06:00 PMCR- 2022/02/07 CRDT- 2022/02/24 05:42 PHST- 2021/11/24 00:00 [received] PHST- 2022/01/13 00:00 [accepted] PHST- 2022/02/24 05:42 [entrez] PHST- 2022/02/25 06:00 [pubmed] PHST- 2022/03/03 06:00 [medline] PHST- 2022/02/07 00:00 [pmc-release] AID - 10.3389/fimmu.2022.821664 [doi] PST - epublish SO - Front Immunol. 2022 Feb 7;13:821664. doi: 10.3389/fimmu.2022.821664. eCollection 2022.