A C57BL/6 Mouse Model of SARS-CoV-2 Infection Recapitulates Age- and Sex-Based Differences in Human COVID-19 Disease and Recovery

Abstract

We present a comprehensive analysis of SARS-CoV-2 infection and recovery using wild type C57BL/6 mice and a mouse-adapted virus, and we demonstrate that this is an ideal model of infection and recovery that phenocopies acute human disease arising from the ancestral SARS-CoV-2. Disease severity and infection kinetics are age- and sex-dependent, as has been reported for humans, with older mice and males in particular exhibiting decreased viral clearance and increased mortality. We identified key parallels with human pathology, including intense virus positivity in bronchial epithelial cells, wide-spread alveolar involvement, recruitment of immune cells to the infected lungs, and acute bronchial epithelial cell death. Moreover, older animals experienced increased virus persistence, delayed dispersal of immune cells into lung parenchyma, and morphologic evidence of tissue damage and inflammation. Parallel analysis of SCID mice revealed that the adaptive immune response was not required for recovery from COVID disease symptoms nor early phase clearance of virus but was required for efficient clearance of virus at later stages of infection. Finally, transcriptional analyses indicated that induction and duration of key innate immune gene programs may explain differences in age-dependent disease severity. Importantly, these data demonstrate that SARS-CoV-2-mediated disease in C57BL/6 mice phenocopies human disease across ages and establishes a platform for future therapeutic and genetic screens for not just SARS-CoV-2 but also novel coronaviruses that have yet to emerge.

BCG administration promotes the long-term protection afforded by a single-dose intranasal adenovirus-based SARS-CoV-2 vaccine

“…For this reason, we challenged the C57BL/6 mice with the B.1.351 strain, capable of binding mACE-2 and establishing infection 58 . Thus, we demonstrated cross-protection delivered by our ancestral strain-based AdV vaccine in a context of SARS-CoV-2 infection, which resembles human disease 59 . However, these mice are not typically used for SARS-CoV-2 vaccine studies, as C57BL/6 mice do not display all the hallmark features of severe pathology and typically recover from infection 60 .…”

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

“…This led to viral replication in the lung and mild respiratory disease (Dinnon et al ., 2020; Leist et al ., 2020). 12-month-old mice were used to recapitulate the more pronounced neuroinflammation observed in middle- and advanced-age COVID-19 patients (Amruta et al, 2022; Davis et al, 2022). At 5 days-post-infection (DPI) mice were euthanized and Cav-1 expression in brain microvessels was assessed by immunostaining ( Figure 1A-C ).…”

BCG administration promotes the long-term protection afforded by a single-dose intranasal adenovirus-based SARS-CoV-2 vaccine

“… 62 Thus, we demonstrated cross-protection delivered by our ancestral strain-based AdV vaccine in a context of SARS-CoV-2 infection due to a heterologous strain, which resembles the situation with human disease. 63 Within this study, we offer insight into the effects of prior BCG immunization on reinforcing vaccine efficacy in a mouse model of SARS-CoV-2. Interestingly, due to the long-term persistence of viable BCG in our experimental design ( Figure S6 ), this study also raises the issue of vaccine efficacy in the context of other persistent bacterial co-infections, as well as components of the normal mucosal microbiota, and represents an important future line of inquiry.…”

“…Although the C57BL/6 mouse model reflects age- and sex-based differences in human COVID-19 disease, 63 it is not the ideal model for SARS-CoV-2 vaccine studies since these mice do not display all the hallmark features of severe pathology and typically recover from infection. 64 As follows, the lung changes observed in our model were modest, posing a limitation in our ability to discriminate severe disease between vaccinated groups.…”