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

Author

Listed:
  • 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
    Chinese Academy of Medical Sciences)

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.

Suggested Citation

  • 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 , 2021. "Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25903-x
    DOI: 10.1038/s41467-021-25903-x
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