PT  - JOURNAL ARTICLE
AU  - Kenneth H. Dinnon III
AU  - Sarah R. Leist
AU  - Alexandra Schäfer
AU  - Caitlin E. Edwards
AU  - David R. Martinez
AU  - Stephanie A. Montgomery
AU  - Ande West
AU  - Boyd L. Yount, Jr
AU  - Yixuan J. Hou
AU  - Lily E. Adams
AU  - Kendra L. Gully
AU  - Ariane J. Brown
AU  - Emily Huang
AU  - Matthew D. Bryant
AU  - Ingrid C. Choong
AU  - Jeffrey S. Glenn
AU  - Lisa E. Gralinski
AU  - Timothy P. Sheahan
AU  - Ralph S. Baric
TI  - A mouse-adapted SARS-CoV-2 model for the evaluation of COVID-19 medical countermeasures
AID  - 10.1101/2020.05.06.081497
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.06.081497
4099  - http://biorxiv.org/content/early/2020/05/07/2020.05.06.081497.short
4100  - http://biorxiv.org/content/early/2020/05/07/2020.05.06.081497.full
AB  - Coronaviruses are prone to emergence into new host species most recently evidenced by SARS-CoV-2, the causative agent of the COVID-19 pandemic. Small animal models that recapitulate SARS-CoV-2 disease are desperately needed to rapidly evaluate medical countermeasures (MCMs). 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. We used reverse genetics to remodel the S and mACE2 binding interface 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 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 IFN lambda-1a treatment in human COVID-19 infections.Competing Interest StatementM.D.B and I.C.C. are employees, and J.S.G is the founder and a board member, of Eiger BioPharmaceuticals, Inc., which produces peg-IFN-λ1.