Characterization of Collaborative Cross mouse founder strain CAST/EiJ as a novel model for lethal COVID-19

Area of Science:

• Virology
• Immunology
• Genetics

Background:

• Mutations in SARS-CoV-2 variants of concern (VOCs) have expanded the virus's host range to include mice.
• Genetically diverse mouse models are needed to understand the varied responses to SARS-CoV-2 infection observed in human populations.

Purpose of the Study:

• To survey the responses to VOC infection in genetically diverse Collaborative Cross (CC) founder strains.
• To identify mouse models that can effectively replicate the spectrum of human COVID-19 disease.

Main Methods:

• Infection of wild-derived Collaborative Cross (CC) founder strains with SARS-CoV-2 VOCs.
• Assessment of viral burden, lung pathology, cytokine profiles, disease susceptibility, and survival.
• Comparison of responses across different inbred mouse strains.

Main Results:

• Collaborative Cross (CC) founder strains exhibited a wide range of viral loads, disease severity, and survival rates.
• Most strains were resistant to severe disease, despite detectable lung viral titers.
• The CAST/EiJ strain developed high lung viral burdens, severe lung pathology, and a dysregulated cytokine response, leading to morbidity and mortality.

Conclusions:

• Genetically diverse mouse strains, particularly CAST/EiJ, provide valuable models for studying SARS-CoV-2 pathogenesis.
• These models can be used to evaluate therapeutic countermeasures against severe COVID-19 and future coronavirus pandemics.