A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures

Dinnon, Kenneth H.; Leist, Sarah R.; Schäfer, Alexandra; Edwards, Caitlin E.; Martinez, David R.; Montgomery, Stephanie A.; West, Ande; Yount, Boyd L.; Hou, Yixuan J.; Adams, Lily E.; Gully, Kendra L.; Brown, Ariane J.; Huang, Emily; Bryant, Matthew D.; Choong, Ingrid C.; Glenn, Jeffrey S.; Gralinski, Lisa E.; Sheahan, Timothy P.; Baric, Ralph S.

Coronaviruses are prone to emergence into new host species most recently evidenced by SARS-CoV-2, the causative agent of the COVID-19 pandemic(1). Small animal models that recapitulate SARS-CoV-2 disease are desperately needed to rapidly evaluate medical countermeasures (MCMs)(2,3). SARS-CoV-2 cannot infect wildtype laboratory mice due to inefficient interactions between the viral spike (S) protein and the murine ortholog of the human receptor, ACE2(4). We used reverse genetics(5) to remodel the interaction between S and mACE2 resulting in a recombinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry. SARS-CoV-2 MA replicated in both the upper and lower airways of both young adult and aged BALB/c mice. Importantly, disease was more severe in aged mice, and showed more clinically relevant phenotypes than those seen in HFH4-hACE2 transgenic mice. We then demonstrated the utility of this model through vaccine challenge studies in immune competent mice with native expression of mACE2. Lastly, we show that clinical candidate interferon (IFN) lambda-1a can potently inhibit SARS-CoV-2 replication in primary human airway epithelial cells in vitro, and both prophylactic and therapeutic administration diminished replication in mice. Our mouse-adapted SARS-CoV-2 model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN lambda-1a treatment in human COVID-19 infections(6).