Generation and Characterization of a SARS-CoV-2-Susceptible Mouse Model Using Adeno-Associated Virus (AAV6.2FF)-Mediated Respiratory Delivery of the Human ACE2 Gene
Nikesh Tailor,
Bryce M. Warner,
Bryan D. Griffin,
Kevin Tierney,
Estella Moffat,
Kathy Frost,
Robert Vendramelli,
Anders Leung,
Marnie Willman,
Sylvia P. Thomas,
Yanlong Pei,
Stephanie A. Booth,
Carissa Embury-Hyatt,
Sarah K. Wootton,
Darwyn Kobasa
Affiliations
Nikesh Tailor
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada
Bryce M. Warner
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada
Bryan D. Griffin
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada
Kevin Tierney
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada
Estella Moffat
National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, 1015 Arlington Street, Winnipeg, MB R3E 3M4, Canada
Kathy Frost
Molecular Pathobiology, National Microbiology Laboratory NML, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
Robert Vendramelli
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada
Anders Leung
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada
Marnie Willman
Department of Medical Microbiology and Infectious Diseases, Faculty of Health Sciences, College of Medicine, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada
Sylvia P. Thomas
Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
Yanlong Pei
Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
Stephanie A. Booth
Molecular Pathobiology, National Microbiology Laboratory NML, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
Carissa Embury-Hyatt
National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, 1015 Arlington Street, Winnipeg, MB R3E 3M4, Canada
Sarah K. Wootton
Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
Darwyn Kobasa
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19) that has caused a pandemic with millions of human infections. There continues to be a pressing need to develop potential therapies and vaccines to inhibit SARS-CoV-2 infection to mitigate the ongoing pandemic. Epidemiological data from the current pandemic indicates that there may be sex-dependent differences in disease outcomes. To investigate these differences, we proposed to use common small animal species that are frequently used to model disease with viruses. However, common laboratory strains of mice are not readily infected by SARS-CoV-2 because of differences in the angiotensin-converting enzyme 2 (ACE2), the cellular receptor for the virus. To overcome this limitation, we transduced common laboratory accessible strains of mice of different sexes and age groups with a novel a triple AAV6 mutant, termed AAV6.2FF, encoding either human ACE2 or luciferase via intranasal administration to promote expression in the lung and nasal turbinates. Infection of AAV-hACE2-transduced mice with SARS-CoV-2 resulted in high viral titers in the lungs and nasal turbinates, establishment of an IgM and IgG antibody response, and modulation of lung and nasal turbinate cytokine profiles. There were insignificant differences in infection characteristics between age groups and sex-related differences; however, there were significant strain-related differences between BALB/c vs. C57BL/6 mice. We show that AAV-hACE2-transduced mice are a useful for determining immune responses and for potential evaluation of SARS-CoV-2 vaccines and antiviral therapies, and this study serves as a model for the utility of this approach to rapidly develop small-animal models for emerging viruses.
