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.
Abstract:
The diversity of COVID-19 disease in otherwise healthy people, from seemingly asymptomatic infection to severe life-threatening disease, is not clearly understood. We passaged a naturally occurring near-ancestral SARS-CoV-2 variant, capable of infecting wild-type mice, and identified viral genomic mutations coinciding with the acquisition of severe disease in young adult mice and lethality in aged animals. Transcriptomic analysis of lung tissues from mice with severe disease elucidated a host antiviral response dominated mainly by interferon and IL-6 pathway activation in young mice, while in aged animals, a fatal outcome was dominated by TNF and TGF-β signaling. Congruent with our pathway analysis, we showed that young TNF-deficient mice had mild disease compared to controls and aged TNF-deficient animals were more likely to survive infection. Emerging clinical correlates of disease are consistent with our preclinical studies, and our model may provide value in defining aberrant host responses that are causative of severe COVID-19.
Insights
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.
