Abstract: “Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19), with effective versus dysregulated responses 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 diverse genetic backgrounds of the Collaborative Cross founder strains crossed to K18-hACE2 transgenic mice that confers high susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 F1 progeny resulted in a spectrum of weight loss, survival, viral replication kinetics, histopathology, and cytokine profiles, some of which were sex-specific. Importantly, survival was associated with early type I interferon (IFN) expression and a phased proinflammatory response distinct from mice with severe disease. Thus, dynamics of inflammatory responses observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding antiviral immunity and evaluating countermeasures.“
Robertson SJ, Bedard O, McNally KL, Lewis M, Clancy C, Shaia C, Broeckel RM, Chiramel AI, Sturdevant GL, Forte E, Preuss C, Baker CN, Harder J, Brunton C, Munger S, Sturdevant DE, Martens C, Holland SM, Rosenthal NA, Best SM. Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation and cytokine responses in COVID-19. bioRxiv [Preprint]. 2022 Feb 24:2021.09.17.460664. doi: 10.1101/2021.09.17.460664. PMID: 35233576; PMCID: PMC8887079.