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

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 m...

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Autores principales: Bader, Stefanie M., Cooney, James P., Sheerin, Dylan, Taiaroa, George, Harty, Leigh, Davidson, Kathryn C., Mackiewicz, Liana, Dayton, Merle, Wilcox, Stephen, Whitehead, Lachlan, Rogers, Kelly L., Georgy, Smitha Rose, Coussens, Anna K., Grimley, Samantha L., Corbin, Vincent, Pitt, Miranda, Coin, Lachlan, Pickering, Raelene, Thomas, Merlin, Allison, Cody C., McAuley, Julie, Purcell, Damian F. J., Doerflinger, Marcel, Pellegrini, Marc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410703/
https://www.ncbi.nlm.nih.gov/pubmed/37523564
http://dx.doi.org/10.1073/pnas.2301689120
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author Bader, Stefanie M.
Cooney, James P.
Sheerin, Dylan
Taiaroa, George
Harty, Leigh
Davidson, Kathryn C.
Mackiewicz, Liana
Dayton, Merle
Wilcox, Stephen
Whitehead, Lachlan
Rogers, Kelly L.
Georgy, Smitha Rose
Coussens, Anna K.
Grimley, Samantha L.
Corbin, Vincent
Pitt, Miranda
Coin, Lachlan
Pickering, Raelene
Thomas, Merlin
Allison, Cody C.
McAuley, Julie
Purcell, Damian F. J.
Doerflinger, Marcel
Pellegrini, Marc
author_facet Bader, Stefanie M.
Cooney, James P.
Sheerin, Dylan
Taiaroa, George
Harty, Leigh
Davidson, Kathryn C.
Mackiewicz, Liana
Dayton, Merle
Wilcox, Stephen
Whitehead, Lachlan
Rogers, Kelly L.
Georgy, Smitha Rose
Coussens, Anna K.
Grimley, Samantha L.
Corbin, Vincent
Pitt, Miranda
Coin, Lachlan
Pickering, Raelene
Thomas, Merlin
Allison, Cody C.
McAuley, Julie
Purcell, Damian F. J.
Doerflinger, Marcel
Pellegrini, Marc
author_sort Bader, Stefanie M.
collection PubMed
description 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.
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spelling pubmed-104107032023-08-10 SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates Bader, Stefanie M. Cooney, James P. Sheerin, Dylan Taiaroa, George Harty, Leigh Davidson, Kathryn C. Mackiewicz, Liana Dayton, Merle Wilcox, Stephen Whitehead, Lachlan Rogers, Kelly L. Georgy, Smitha Rose Coussens, Anna K. Grimley, Samantha L. Corbin, Vincent Pitt, Miranda Coin, Lachlan Pickering, Raelene Thomas, Merlin Allison, Cody C. McAuley, Julie Purcell, Damian F. J. Doerflinger, Marcel Pellegrini, Marc Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2023-07-31 2023-08-08 /pmc/articles/PMC10410703/ /pubmed/37523564 http://dx.doi.org/10.1073/pnas.2301689120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Bader, Stefanie M.
Cooney, James P.
Sheerin, Dylan
Taiaroa, George
Harty, Leigh
Davidson, Kathryn C.
Mackiewicz, Liana
Dayton, Merle
Wilcox, Stephen
Whitehead, Lachlan
Rogers, Kelly L.
Georgy, Smitha Rose
Coussens, Anna K.
Grimley, Samantha L.
Corbin, Vincent
Pitt, Miranda
Coin, Lachlan
Pickering, Raelene
Thomas, Merlin
Allison, Cody C.
McAuley, Julie
Purcell, Damian F. J.
Doerflinger, Marcel
Pellegrini, Marc
SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates
title SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates
title_full SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates
title_fullStr SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates
title_full_unstemmed SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates
title_short SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates
title_sort sars-cov-2 mouse adaptation selects virulence mutations that cause tnf-driven age-dependent severe disease with human correlates
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410703/
https://www.ncbi.nlm.nih.gov/pubmed/37523564
http://dx.doi.org/10.1073/pnas.2301689120
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