Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2

Shihui Sun, Hongjing Gu, Lei Cao, Qi Chen, Qing Ye, Guan Yang, Rui-Ting Li, Hang Fan, Yong-Qiang Deng, Xiaopeng Song, Yini Qi, Min Li, Jun Lan, Rui Feng, Yan Guo, Na Zhu, Si Qin, Lei Wang, Yi-Fei Zhang, Chao Zhou, Lingna Zhao, Yuehong Chen, Meng Shen, Yujun Cui, Xiao Yang, Xinquan Wang, Wenjie Tan, Hui Wang (), Xiangxi Wang () and Cheng-Feng Qin ()
Additional contact information
Shihui Sun: Beijing Institute of Microbiology and Epidemiology, AMMS
Hongjing Gu: Beijing Institute of Microbiology and Epidemiology, AMMS
Lei Cao: Chinese Academy of Sciences
Qi Chen: Beijing Institute of Microbiology and Epidemiology, AMMS
Qing Ye: Beijing Institute of Microbiology and Epidemiology, AMMS
Guan Yang: Beijing Institute of Lifeomics
Rui-Ting Li: Beijing Institute of Microbiology and Epidemiology, AMMS
Hang Fan: Beijing Institute of Microbiology and Epidemiology, AMMS
Yong-Qiang Deng: Beijing Institute of Microbiology and Epidemiology, AMMS
Xiaopeng Song: Beijing Institute of Lifeomics
Yini Qi: Beijing Institute of Lifeomics
Min Li: Beijing Institute of Microbiology and Epidemiology, AMMS
Jun Lan: Chinese Academy of Sciences
Rui Feng: Chinese Academy of Sciences
Yan Guo: Beijing Institute of Microbiology and Epidemiology, AMMS
Na Zhu: Chinese Center for Disease Control and Prevention (China CDC)
Si Qin: Beijing Institute of Microbiology and Epidemiology, AMMS
Lei Wang: Chinese Academy of Sciences
Yi-Fei Zhang: Beijing Institute of Microbiology and Epidemiology, AMMS
Chao Zhou: Beijing Institute of Microbiology and Epidemiology, AMMS
Lingna Zhao: Beijing Institute of Microbiology and Epidemiology, AMMS
Yuehong Chen: Beijing Institute of Microbiology and Epidemiology, AMMS
Meng Shen: Beijing Institute of Microbiology and Epidemiology, AMMS
Yujun Cui: Beijing Institute of Microbiology and Epidemiology, AMMS
Xiao Yang: Beijing Institute of Lifeomics
Xinquan Wang: Tsinghua University
Wenjie Tan: Chinese Center for Disease Control and Prevention (China CDC)
Hui Wang: Beijing Institute of Microbiology and Epidemiology, AMMS
Xiangxi Wang: Chinese Academy of Sciences
Cheng-Feng Qin: Beijing Institute of Microbiology and Epidemiology, AMMS

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract There is an urgent need for animal models to study SARS-CoV-2 pathogenicity. Here, we generate and characterize a novel mouse-adapted SARS-CoV-2 strain, MASCp36, that causes severe respiratory symptoms, and mortality. Our model exhibits age- and gender-related mortality akin to severe COVID-19. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three RBD mutations significantly enhance binding affinity to its endogenous receptor, ACE2. Cryo-electron microscopy analysis of human ACE2 (hACE2), or mouse ACE2 (mACE2), in complex with the RBD of MASCp36, at 3.1 to 3.7 Å resolution, reveals the molecular basis for the receptor-binding switch. N501Y and Q493H enhance the binding affinity to hACE2, whereas triple mutations at N501Y/Q493H/K417N decrease affinity and reduce infectivity of MASCp36. Our study provides a platform for studying SARS-CoV-2 pathogenesis, and unveils the molecular mechanism for its rapid adaptation and evolution.

Date: 2021
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DOI: 10.1038/s41467-021-25903-x

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