RT Journal Article
SR Electronic
T1 A mouse-adapted SARS-CoV-2 model for the evaluation of COVID-19 medical countermeasures
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.06.081497
DO 10.1101/2020.05.06.081497
A1 Kenneth H. Dinnon III
A1 Sarah R. Leist
A1 Alexandra Schäfer
A1 Caitlin E. Edwards
A1 David R. Martinez
A1 Stephanie A. Montgomery
A1 Ande West
A1 Boyd L. Yount, Jr
A1 Yixuan J. Hou
A1 Lily E. Adams
A1 Kendra L. Gully
A1 Ariane J. Brown
A1 Emily Huang
A1 Matthew D. Bryant
A1 Ingrid C. Choong
A1 Jeffrey S. Glenn
A1 Lisa E. Gralinski
A1 Timothy P. Sheahan
A1 Ralph S. Baric
YR 2020
UL http://biorxiv.org/content/early/2020/05/07/2020.05.06.081497.abstract
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.