SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates

Bader, SM; Cooney, JP; Sheerin, D; Taiaroa, G; Harty, L; Davidson, KC; Mackiewicz, L; Dayton, M; Wilcox, S; Whitehead, L; Rogers, KL; Georgy, SR; Coussens, AK; Grimley, SL; Corbin, V; Pitt, M; Coin, L; Pickering, R; Thomas, M; Allison, CC; McAuley, J; Purcell, DFJ; Doerflinger, M; Pellegrini, M

Author(s): Bader, SM; Cooney, JP; Sheerin, D; Taiaroa, G; Harty, L; Davidson, KC; Mackiewicz, L; Dayton, M; Wilcox, S; Whitehead, L; Rogers, KL; Georgy, SR; Coussens, AK; Grimley, SL; Corbin, V; Pitt, M; Coin, L; Pickering, R; Thomas, M; Allison, CC; McAuley, J; Purcell, DFJ; Doerflinger, M; Pellegrini, M;
Details: Publication Year 2023-08-08,Volume 120,Issue #32,Page e2301689120
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
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.
Keywords: Young Adult; Humans; Mice; Animals; Aged; *SARS-CoV-2/genetics; *COVID-19/genetics; Virulence/genetics; Mutation; Disease Models, Animal; Covid-19; SARS-CoV-2; cytokines; inflammation; mouse adapted
Research Division(s): Advanced Technology And Biology; Infectious Diseases And Immune Defence
PubMed ID: 37523564
Publisher's Version: https://doi.org/10.1073/pnas.2301689120
Open Access at Publisher's Site: https://doi.org/10.1073/pnas.2301689120
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-08-04 12:44:14

Last Modified: 2023-08-04 01:37:47