OmniVira

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

Shihui Sun1 Hongjing Gu1 Lei Cao2 Qi Chen1 Qing Ye1 Guan Yang3 Rui-Ting Li1 Hang Fan1 Yong-Qiang Deng1 Xiaopeng Song3 Yini Qi3 Min Li1 Jun Lan2 Rui Feng2 Yan Guo1 Na Zhu4 Si Qin1 Lei Wang2 Yi-Fei Zhang1 Chao Zhou1 Lingna Zhao1 Yuehong Chen1 Meng Shen1 Yujun Cui1 Xiao Yang3 Xinquan Wang5 Wenjie Tan4 Hui Wang6 Xiangxi Wang7 Cheng-Feng Qin8,9
Affiliations 9 institutions
  1. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, AMMS, Beijing, 100071, China.
  2. CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  3. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
  4. National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing, 102206, China.
  5. The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  6. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, AMMS, Beijing, 100071, China. [email protected].
  7. CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  8. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, AMMS, Beijing, 100071, China. [email protected].
  9. Research Unit of Discovery and Tracing of Natural Focus Diseases, Chinese Academy of Medical Sciences, Beijing, 100071, China. [email protected].
PMID34580297 DOI10.1038/s41467-021-25903-x Year2021 Journal Nature communications Nat Commun Languageeng Statusepublish

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.

Supporting text Virus Host Location
Amino Acid Substitution 81 Angiotensin-Converting Enzyme 2 177 Animals 1948 Binding Sites 89 COVID-19 425 Disease Models, Animal 77 Female 289 Humans 1440 Male 224 Mice 253 Protein Binding 193 Protein Domains 45 SARS-CoV-2 453 Severity of Illness Index 2 Spike Glycoprotein, Coronavirus 274 Ace2 protein, mouse 16 spike protein, SARS-CoV-2 157

Evidence records

2 total
Experimental Infection
1 records · 1 evidence types
Evidence type Pathogenicity Experiment
1 records
OVE5186 Pathogenicity Experiment
Key finding

The mouse-adapted SARS-CoV-2 strain MASCp36 caused severe respiratory symptoms and mortality in experimentally infected mice, showing age- and gender-related disease severity.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
house mouse Mus musculus Experimental system
Location
Not specified
Supporting text

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.

Method
experimental infection in mice | clinical observation of respiratory symptoms | mortality assessment
Experimental system
mouse infection model
Functional Mechanism
1 records · 1 evidence types
Evidence type Molecular Adaptation
1 records
OVE5187 Molecular Adaptation
Key finding

Three amino acid substitutions (N501Y, Q493H, K417N) in the receptor binding domain of the mouse-adapted SARS-CoV-2 strain MASCp36 enhance ACE2 binding affinity, revealing molecular adaptation in receptor interaction.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

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.

Genes or proteins
receptor binding domain | RBD
Receptors
ACE2
Mutations
N501Y | Q493H | K417N
Mechanism types
receptor binding | host-range expansion