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

Area of Science:

• Virology
• Pathogen Adaptation
• Animal Models

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenicity requires effective animal models for study.
• Existing models may not fully recapitulate human disease severity or age/gender-related mortality observed in COVID-19.

Purpose of the Study:

• To generate and characterize a novel mouse-adapted SARS-CoV-2 strain for studying viral pathogenicity.
• To elucidate the molecular mechanisms underlying SARS-CoV-2 adaptation and evolution in vivo.

Main Methods:

• Generation and characterization of a mouse-adapted SARS-CoV-2 strain (MASCp36).
• Deep sequencing to identify mutations in the receptor-binding domain (RBD).
• Cryo-electron microscopy to analyze the structural basis of ACE2-RBD interactions.

Main Results:

• MASCp36 causes severe respiratory symptoms and mortality in mice, with age- and gender-related patterns similar to human COVID-19.
• Three key amino acid substitutions (N501Y, Q493H, K417N) were identified in the RBD of MASCp36.
• These mutations enhance binding affinity to mouse ACE2, while specific combinations affect human ACE2 binding and viral infectivity.

Conclusions:

• MASCp36 serves as a valuable platform for SARS-CoV-2 pathogenesis research.
• The study reveals the molecular basis for SARS-CoV-2 adaptation, including the role of specific RBD mutations in receptor binding and viral evolution.