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A mouse-adapted SARS-CoV-2 model for the evaluation of COVID-19 medical countermeasures

View ORCID ProfileKenneth H. Dinnon III, View ORCID ProfileSarah R. Leist, Alexandra Schäfer, View ORCID ProfileCaitlin E. Edwards, David R. Martinez, Stephanie A. Montgomery, Ande West, Boyd L. Yount Jr, View ORCID ProfileYixuan J. Hou, Lily E. Adams, Kendra L. Gully, Ariane J. Brown, Emily Huang, Matthew D. Bryant, Ingrid C. Choong, Jeffrey S. Glenn, View ORCID ProfileLisa E. Gralinski, View ORCID ProfileTimothy P. Sheahan, View ORCID ProfileRalph S. Baric
doi: https://doi.org/10.1101/2020.05.06.081497
Kenneth H. Dinnon III
1Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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  • ORCID record for Kenneth H. Dinnon III
Sarah R. Leist
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Alexandra Schäfer
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Caitlin E. Edwards
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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David R. Martinez
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Stephanie A. Montgomery
3Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
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Ande West
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Boyd L. Yount Jr
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Yixuan J. Hou
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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  • ORCID record for Yixuan J. Hou
Lily E. Adams
1Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Kendra L. Gully
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Ariane J. Brown
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Emily Huang
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Matthew D. Bryant
4Eiger BioPharmaceuticals, Inc., Palo Alto, CA, USA
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Ingrid C. Choong
4Eiger BioPharmaceuticals, Inc., Palo Alto, CA, USA
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Jeffrey S. Glenn
5Departments of Medicine and Microbiology & Immunology, Stanford University, Stanford, CA, USA
6Palo Alto Veterans Administration, Palo Alto, CA, USA
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Lisa E. Gralinski
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Timothy P. Sheahan
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Ralph S. Baric
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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  • For correspondence: rbaric@email.unc.edu
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Abstract

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 Statement

M.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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 07, 2020.
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A mouse-adapted SARS-CoV-2 model for the evaluation of COVID-19 medical countermeasures
Kenneth H. Dinnon III, Sarah R. Leist, Alexandra Schäfer, Caitlin E. Edwards, David R. Martinez, Stephanie A. Montgomery, Ande West, Boyd L. Yount Jr, 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, Ralph S. Baric
bioRxiv 2020.05.06.081497; doi: https://doi.org/10.1101/2020.05.06.081497
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A mouse-adapted SARS-CoV-2 model for the evaluation of COVID-19 medical countermeasures
Kenneth H. Dinnon III, Sarah R. Leist, Alexandra Schäfer, Caitlin E. Edwards, David R. Martinez, Stephanie A. Montgomery, Ande West, Boyd L. Yount Jr, 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, Ralph S. Baric
bioRxiv 2020.05.06.081497; doi: https://doi.org/10.1101/2020.05.06.081497

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