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Comparison of Transgenic and Adenovirus hACE2 Mouse Models for SARS-CoV-2 Infection

RaveenRathnasinghe,ShirinStrohmeier,FatimaAmanat,Virginia L.Gillespie,FlorianKrammer,AdolfoGarcía-Sastre,LyndaCoughlan,MichaelSchotsaert,MelissaUccellini
doi: https://doi.org/10.1101/2020.07.06.190066
Raveen Rathnasinghe
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
2Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
3Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
Shirin Strohmeier
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
3Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
Fatima Amanat
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
3Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
Virginia L. Gillespie
4The Center for Comparative Medicine and Surgery (CCMS) Comparative Pathology Laboratory, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
Florian Krammer
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
Adolfo García-Sastre
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
2Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
6The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
Lynda Coughlan
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
Michael Schotsaert
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
2Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
Melissa Uccellini
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
2Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029,USA
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Abstract

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide pandemic with high morbidity and mortality. Development of animal models that recapitulate important aspects of coronavirus disease 2019 (COVID-19) is critical for the evaluation of vaccines and antivirals, and understanding disease pathogenesis. SARS-CoV-2 has been shown to use the same entry receptor as SARS-CoV-1, human angiotensin-converting enzyme 2 (hACE2)(1-3). Due to amino acid differences between murine and hACE2, inbred mouse strains fail to support high titer viral replication of SARS-CoV-2 virus. Therefore, a number of transgenic and knock-in mouse models, as well as viral vector-mediated hACE2 delivery systems have been developed. Here we compared the K18-hACE2 transgenic model to adenovirus-mediated delivery of hACE2 to the mouse lung. We show that K18-hACE2 mice replicate virus to high titers in both the lung and brain leading to lethality. In contrast, adenovirus-mediated delivery results in viral replication to lower titers limited to the lung, and no clinical signs of infection with a challenge dose of 104 plaque forming units. The K18-hACE2 model provides a stringent model for testing the ability of vaccines and antivirals to protect against disease, whereas the adenovirus delivery system has the flexibility to be used across multiple genetic backgrounds and modified mouse strains.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
Posted July 06, 2020.
Comparison of Transgenic and Adenovirus hACE2 Mouse Models for SARS-CoV-2 Infection
RaveenRathnasinghe,ShirinStrohmeier,FatimaAmanat,Virginia L.Gillespie,FlorianKrammer,AdolfoGarcía-Sastre,LyndaCoughlan,MichaelSchotsaert,MelissaUccellini
bioRxiv2020.07.06.190066;doi: https://doi.org/10.1101/2020.07.06.190066
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