AUTHOR=Nakandakari-Higa Sandra , Parsa Roham , Reis Bernardo S. , de Carvalho Renan V. H. , Mesin Luka , Hoffmann Hans-Heinrich , Bortolatto Juliana , Muramatsu Hiromi , Lin Paulo. J. C. , Bilate Angelina M. , Rice Charles M. , Pardi Norbert , Mucida Daniel , Victora Gabriel D. , Canesso Maria Cecilia C. 

TITLE=A minimally-edited mouse model for infection with multiple SARS-CoV-2 strains

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1007080

DOI=10.3389/fimmu.2022.1007080

ISSN=1664-3224

ABSTRACT=<p>Efficient mouse models to study SARS-CoV-2 infection are critical for the development and assessment of vaccines and therapeutic approaches to mitigate the current pandemic and prevent reemergence of COVID-19. While the first generation of mouse models allowed SARS-CoV-2 infection and pathogenesis, they relied on ectopic expression and non-physiological levels of human angiotensin-converting enzyme 2 (hACE2). Here we generated a mouse model carrying the minimal set of modifications necessary for productive infection with multiple strains of SARS-CoV-2. Substitution of only three amino acids in the otherwise native mouse <italic>Ace2</italic> locus (<italic>Ace2</italic><sup>TripleMutant</sup> or <italic>Ace2</italic>™), was sufficient to render mice susceptible to both SARS-CoV-2 strains USA-WA1/2020 and B.1.1.529 (Omicron). Infected <italic>Ace2</italic>™ mice exhibited weight loss and lung damage and inflammation, similar to COVID-19 patients. Previous exposure to USA-WA1/2020 or mRNA vaccination generated memory B cells that participated in plasmablast responses during breakthrough B.1.1.529 infection. Thus, the <italic>Ace2</italic>™ mouse replicates human disease after SARS-CoV-2 infection and provides a tool to study immune responses to sequential infections in mice.</p>