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

Kenneth H. Dinnon, Sarah R. Leist, Alexandra Schäfer, Caitlin E. Edwards, David R. Martinez, Stephanie A. Montgomery, Ande West, Boyd L. Yount, Yixuan J. Hou, Lily E. Adams, Kendra L. Gully, Ariane J. Brown, Emily Huang, Matthew D. Bryant, Ingrid C. Choong, Jeffrey S. Glenn, Lisa E. Gralinski, Timothy P. Sheahan and Ralph S. Baric ()
Additional contact information
Kenneth H. Dinnon: University of North Carolina at Chapel Hill
Sarah R. Leist: University of North Carolina at Chapel Hill
Alexandra Schäfer: University of North Carolina at Chapel Hill
Caitlin E. Edwards: University of North Carolina at Chapel Hill
David R. Martinez: University of North Carolina at Chapel Hill
Stephanie A. Montgomery: University of North Carolina
Ande West: University of North Carolina at Chapel Hill
Boyd L. Yount: University of North Carolina at Chapel Hill
Yixuan J. Hou: University of North Carolina at Chapel Hill
Lily E. Adams: University of North Carolina at Chapel Hill
Kendra L. Gully: University of North Carolina at Chapel Hill
Ariane J. Brown: University of North Carolina at Chapel Hill
Emily Huang: University of North Carolina at Chapel Hill
Matthew D. Bryant: Eiger BioPharmaceuticals
Ingrid C. Choong: Eiger BioPharmaceuticals
Jeffrey S. Glenn: Stanford University
Lisa E. Gralinski: University of North Carolina at Chapel Hill
Timothy P. Sheahan: University of North Carolina at Chapel Hill
Ralph S. Baric: University of North Carolina at Chapel Hill

Nature, 2020, vol. 586, issue 7830, 560-566

Abstract: Abstract Coronaviruses are prone to transmission to new host species, as recently demonstrated by the spread to humans of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic1. Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures2,3. SARS-CoV-2 cannot infect wild-type laboratory mice owing to inefficient interactions between the viral spike protein and the mouse orthologue of the human receptor, angiotensin-converting enzyme 2 (ACE2)4. Here we used reverse genetics5 to remodel the interaction between SARS-CoV-2 spike protein and mouse ACE2 and designed mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA), a recombinant virus that can use mouse ACE2 for entry into cells. SARS-CoV-2 MA was able to replicate in the upper and lower airways of both young adult and aged BALB/c mice. SARS-CoV-2 MA caused more severe disease in aged mice, and exhibited more clinically relevant phenotypes than those seen in Hfh4-ACE2 transgenic mice, which express human ACE2 under the control of the Hfh4 (also known as Foxj1) promoter. We demonstrate the utility of this model using vaccine-challenge studies in immune-competent mice with native expression of mouse ACE2. Finally, we show that the clinical candidate interferon-λ1a (IFN-λ1a) potently inhibits SARS-CoV-2 replication in primary human airway epithelial cells in vitro—both prophylactic and therapeutic administration of IFN-λ1a diminished SARS-CoV-2 replication in mice. In summary, the mouse-adapted SARS-CoV-2 MA model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN-λ1a as a treatment for human COVID-196.

Date: 2020
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DOI: 10.1038/s41586-020-2708-8

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