MODELING DISEASE: THE AGING IMMUNE SYSTEM AND SARS-COV-2

Abstract

SARS-CoV-2 is a single stranded RNA coronavirus that causes the coronavirus-19 disease (COVID-19). People infected with the virus may experience mild symptoms such as fever, cough, nausea, or severe outcomes including acute respiratory distress syndrome (ARDS), cytokine storm, and death. One major determinant of disease severity is age; the presence of agerelated co-morbidities including, but not limited to, diabetes, pulmonary fibrosis, hypertension, and atherosclerosis, represent additional independent risk factors for severe COVID-19. Although many advances have been made in understanding and treating COVID-19, there are significant knowledge gaps in understanding its basic pathogenesis, including mechanisms responsible for the differences in health outcomes with regards to aging. The purpose of this study was to characterize mouse models of SARS-CoV-2 infection to study the effects of aging on disease pathogenesis and susceptibility. In furtherance of these goals, we used two different models: 1) a mouse-adapted SARS-CoV-2 strain to infect B57BL/6 mice and 2) a transgenic mouse expressing the human homolog of the viral entry receptor, ACE2, which allows for infection of mice with clinical virus isolates. In the mouse-adapted model, we found old mice to be more susceptible to SARS-CoV-2 when compared to adult mice. Specifically, we detected increased viral burden in the lungs of old mice, with increased mortality and higher weight loss following infection compared to adult mice. In the hACE2 transgenic model, we demonstrated that increased copy numbers of hACE2 receptor expression increased the mortality and weight loss indicating more severe disease. Specifically, following infection with 103 SARS-CoV-2 strain WA-1/2020 plaque-forming units, all 8-gene copy hACE2 mice perished within 11 days. Survival was higher (30.7%) in 2-copy hACE2 Tg mice whereas 1-copy mice were resistant to this dose of infection. We conclude that both mouse models will be informative to the studies of the impact of age-related changes in the adaptive immune system as related to SARS-CoV-2 disease susceptibility and severity.