SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human
Stefanie M Bader1,2, James P Cooney1,2, Dylan Sheerin1,2
1The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia.
Summary
Researchers identified genetic changes in SARS-CoV-2 that cause severe COVID-19 in mice. Different immune responses in young and aged mice, involving pathways like TNF, influenced disease severity and survival.
Area of Science:
- Virology
- Immunology
- Pathogenesis
Background:
- The variable severity of COVID-19, from asymptomatic to critical illness, remains poorly understood.
- Identifying host and viral factors contributing to severe disease is crucial for therapeutic development.
Purpose of the Study:
- To investigate the viral and host factors underlying diverse COVID-19 disease severity.
- To develop a preclinical model for studying severe COVID-19 pathogenesis.
Main Methods:
- Passaging of a SARS-CoV-2 variant in wild-type mice to select for mutations associated with severe disease.
- Transcriptomic analysis of mouse lung tissues to identify host immune response pathways.
- Evaluation of disease severity and survival in genetically modified (TNF-deficient) mice.
Main Results:
- Viral genomic mutations were identified that correlated with severe disease in young mice and lethality in aged mice.
- Young mice exhibited interferon and IL-6 pathway activation, while aged mice showed TNF and TGF-β signaling dominance.
- TNF-deficient young mice had milder disease, and aged TNF-deficient mice demonstrated increased survival rates.
Conclusions:
- Aberrant host immune responses, particularly involving TNF signaling, contribute significantly to severe COVID-19 outcomes.
- This mouse model effectively recapitulates aspects of human COVID-19 severity and can be used to study disease mechanisms.
