A Mouse Model of SARS-CoV-2 induced Acute Lung Injury (ALI) in Standard Laboratory Mice

Due to their zoonotic nature coronaviruses are poised for emergence into new species. Most recently, SARS-CoV-2 emerged into humans in Wuhan, China to cause a worldwide pandemic leading to significant morbidity, mortality and economic losses. As SARS-CoV-2 cannot infect standard laboratory mice there is an urgent need for small animal models that accurately reflect the spectrum of disease symptoms observed in humans. We used an in vivo passaging strategy to further adapt a SARS-CoV-2 virus variant that was genetically engineered to allow for efficient binding of the viral spike protein to the mACE2 receptor for entry. After 10 passages we recovered a virus (SARS-CoV-2 MA10) that is able to cause significant morbidity and mortality in young adult BALB/c mice. Additionally, aged BALB/c mice exhibited an increase in disease phenotypes as it has been observed in humans. Histopathological and lung function analyses revealed that morbidity and mortality in those models is caused by a decrease in lung function including hallmarks of acute lung injury (ALI) and acute respiratory distress symptoms (ARDS). Furthermore, we challenged C57BL/6J mice with SARS-CoV-2 MA10, which are the most commonly used inbred mouse strain and serve as the genetic backbone for the majority of genetically engineered mice. We observed an attenuated disease phenotype giving the field the opportunity to analyze increase as well as decrease of pathogenicity. We then showed that SARS-CoV-2 is an ideal model to test medical counter measurements including clinical parameters of disease. Mice vaccinated with VRPs expressing the spike protein were protected from weight loss and decreased lung function. Overall, we generated and characterized a new mouse adapted SARS-CoV-2 model that mirrors multiple aspects of COVID-19 disease seen in humans including age-related increase in morbidity and mortality, targeting of cells in upper and lower respiratory tract, and respiratory dysfunction. Thus, our model fulfills the urgent need for a small animal model that provides robust parameters to evaluate medical counter measurements such as vaccines and antivirals.