Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19

Shelly J. Robertson, Olivia Bedard, Kristin L. McNally, Carl Shaia, Chad S. Clancy, Matthew Lewis, Rebecca M. Broeckel, Abhilash I. Chiramel, Jeffrey G. Shannon, Gail L. Sturdevant, Rebecca Rosenke, Sarah L. Anzick, Elvira Forte, Christoph Preuss, Candice N. Baker, Jeffrey M. Harder, Catherine Brunton, Steven Munger, Daniel P. Bruno, Justin B. Lack, Jacqueline M. Leung, Amirhossein Shamsaddini, Paul Gardina, Daniel E. Sturdevant, Jian Sun, Craig Martens, Steven M. Holland, Nadia A. Rosenthal () and Sonja M. Best ()
Additional contact information
Shelly J. Robertson: National Institute of Allergy and Infectious Diseases, NIH
Olivia Bedard: The Jackson Laboratory
Kristin L. McNally: National Institute of Allergy and Infectious Diseases, NIH
Carl Shaia: National Institute of Allergy and Infectious Diseases, NIH
Chad S. Clancy: National Institute of Allergy and Infectious Diseases, NIH
Matthew Lewis: National Institute of Allergy and Infectious Diseases, NIH
Rebecca M. Broeckel: National Institute of Allergy and Infectious Diseases, NIH
Abhilash I. Chiramel: National Institute of Allergy and Infectious Diseases, NIH
Jeffrey G. Shannon: National Institute of Allergy and Infectious Diseases, NIH
Gail L. Sturdevant: National Institute of Allergy and Infectious Diseases, NIH
Rebecca Rosenke: National Institute of Allergy and Infectious Diseases, NIH
Sarah L. Anzick: National Institute of Allergy and Infectious Diseases, NIH
Elvira Forte: The Jackson Laboratory
Christoph Preuss: The Jackson Laboratory
Candice N. Baker: The Jackson Laboratory
Jeffrey M. Harder: The Jackson Laboratory
Catherine Brunton: The Jackson Laboratory
Steven Munger: The Jackson Laboratory
Daniel P. Bruno: National Institute of Allergy and Infectious Diseases, NIH
Justin B. Lack: National Institute of Allergy and Infectious Diseases, NIH
Jacqueline M. Leung: National Institute of Allergy and Infectious Diseases, NIH
Amirhossein Shamsaddini: National Institute of Allergy and Infectious Diseases, NIH
Paul Gardina: National Institute of Allergy and Infectious Diseases, NIH
Daniel E. Sturdevant: National Institute of Allergy and Infectious Diseases, NIH
Jian Sun: National Institute of Allergy and Infectious Diseases, NIH
Craig Martens: National Institute of Allergy and Infectious Diseases, NIH
Steven M. Holland: National Institute of Allergy and Infectious Diseases, NIH
Nadia A. Rosenthal: The Jackson Laboratory
Sonja M. Best: National Institute of Allergy and Infectious Diseases, NIH

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to disease. Thus, virus dynamics and inflammation observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding anti-coronavirus immunity.

Date: 2023
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DOI: 10.1038/s41467-023-40076-5

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