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Literature detail

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].
PMID 34580297 2021 Nat Commun eng epublish
PubMed DOI Browse context

Article

Publication summary

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.

Amino Acid Substitution Angiotensin-Converting Enzyme 2 Animals Binding Sites COVID-19 Disease Models, Animal Female Humans Male Mice Protein Binding Protein Domains SARS-CoV-2 Severity of Illness Index Spike Glycoprotein, Coronavirus Ace2 protein, mouse spike protein, SARS-CoV-2

Structured evidence records

Evidence records

4 total
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.85
Key finding

Three RBD mutations (N501Y, Q493H, K417N) emerged in the mouse-adapted SARS-CoV-2 strain MASCp36 during in vivo passaging, indicating viral genetic evolution associated with adaptation to mice.

Virus
SARS-CoV-2
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.

Genes or proteins
receptor binding domain; spike glycoprotein
Analysis methods
deep sequencing
Host Range Experiment 1 records
Host Range Experiment Extraction confidence 0.90
Key finding

A mouse-adapted SARS-CoV-2 strain (MASCp36) was experimentally obtained that lethally infects mice and shows altered receptor binding affinity conferring adaptation to mouse ACE2.

Virus
SARS-CoV-2
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. Deep sequencing identified three amino acid substitutions ... during in vivo passaging. Cryo-electron microscopy analysis of human ACE2 or mouse ACE2 in complex with the RBD of MASCp36 reveals the molecular basis for the receptor-binding switch.

Method
in vivo passaging; experimental infection; structural analysis; receptor-binding assay
Sample type
respiratory tract
Experimental system
in vivo animal experiment
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.98
Key finding

Mutations N501Y, Q493H, and K417N in the RBD of MASCp36 enhance ACE2 binding, providing a molecular basis for SARS-CoV-2 adaptation to mice.

Virus
SARS-CoV-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
Spike Glycoprotein; Receptor Binding Domain
Receptors
ACE2
Mutations
N501Y; Q493H; K417N
Mechanism types
receptor_binding; host_adaptation; pathogenicity
Receptor Usage 1 records
Receptor Usage Extraction confidence 0.95
Key finding

Mutations N501Y, Q493H, and K417N in the RBD of mouse-adapted SARS-CoV-2 strain MASCp36 modulate the binding affinity to human and mouse ACE2 receptors, revealing a receptor-binding switch underlying adaptation.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, at the receptor binding domain (RBD) of MASCp36. 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 reveals the molecular basis for the receptor-binding switch.

Method
deep sequencing; cryo-electron microscopy; binding affinity analysis
Receptors
ACE2