SARS-CoV-2 infection causes heightened disease severity and mortality in a mouse model of Down syndrome
Recent epidemiological studies suggest that individuals with Down syndrome are more susceptible to SARS-CoV-2 infection and have higher rates of hospitalization and mortality than the general population. However, the main drivers behind these disparate health outcomes remain unknown. Herein we performed experimental infections with SARS-CoV-2 in a well-established mouse model of Down syndrome, Dp(16)1Yey/+;Tg(K18-ACE2)2Prlmn/+ (abbreviated as Dp16;ACE2). We observed similar SARS-CoV-2 replication kinetics and dissemination in the primary and secondary organs between mice with and without Down syndrome (i.e., Dp16;ACE2 and ACE2), suggesting that both groups have similar susceptibilities to SARS-CoV-2 infection. However, Down syndrome mice exhibited more severe disease as defined by clinical features including symptoms, weight loss, pulmonary function, and survival of mice. We found that increased disease severity in Down syndrome mice could not be attributed solely to increased infectivity or a more dramatic pro-inflammatory response to infection. Rather, results from RNA sequencing suggested that differences in expression of genes from other physiological pathways such as deficient oxidative phosphorylation, cardiopulmonary dysfunction and deficient mucociliary clearance in the lungs may also contribute to heightened disease severity and mortality in Down syndrome mice following SARS-CoV-2 infection. Overall design: To investigate whether individuals with Down syndrome are more susceptible to SARS-CoV-2 infection and have more severe COVID-19 in a mouse model of Down syndrome, we made a mutant mouse strain (Dp16;ACE2 or DS) by crossing Dp16 mouse, which has Down syndrome features, and ACE2 mouse (WT), which expresses human ACE2 gene and is susceptible to SARS-CoV-2 infection. We then performed gene expression profiling analysis using data obtained from RNA-seq of the two mouse mutants either mock-infected or infected with SARS-CoV-2 at 2 different time points.