Coronaviruses remain a constant threat to human health, and since 2003, three novel coronaviruses have emerged causing severe disease in humans. In 2003, the severe acute respiratory syndrome coronavirus (SARS-CoV) caused over 8,000 infections and about 800 deaths worldwide. This was followed in 2012 by the Middle East respiratory syndrome coronavirus (MERS-CoV), which has caused over 2,500 cases and 900 deaths. Finally, there is the ongoing global COVID-19 pandemic, which started in 2019 and is caused by SARS-CoV-2.
SARS-CoV-2 binds to the angiotensin-converting enzyme 2 in humans (hACE2) for docking and entry into cells but is unable to use the murine ortholog (mACE2) in a similar fashion. SARS-CoV-2 mouse models expressing hACE2 have been generated, however these models do not accurately recapitulate the symptoms of COVID-19 that are observed in humans (e.g. severe lung disease). This highlights the need for the development of tools that can be used to study COVID-19 in mice that more accurately represent the clinical symptoms in humans for evaluation of potential vaccine and anti-viral treatments.
Researchers in the Department of Epidemiology have developed two mouse adapted strains of SARS-CoV-2 (SARS-CoV-2 MA and SARS-CoV-2 MA10) that accurately reproduce in mice the clinical symptoms observed in humans. The interaction of the SARS-CoV-2 spike protein and the mouse ACE2 receptor was modified which allows SARS-CoV-2 MA and SARS-CoV-2 MA10 to use the mouse ACE2 receptor for entry into cells. Mice infected with SARS-CoV-2 MA reproduce clinical symptoms observed in humans including more severe disease in aged mice, viral replication in the upper and lower airways, and development of the relevant pulmonary lesions of acute lung injury (including pneumonitis, edema, necrotic debris, and hyaline membrane formation) that are consistent with progression to acute respiratory distress syndrome (ARDS). However, young mice infected with SARS-CoV-2 MA do not reproduce the clinical signs of acute lung injury. A second mouse adapted strain, SARS-CoV-2 MA10, was developed which reproduces clinical symptoms (severe disease in aged mice, lung injury, ARDS, etc.) in young and aged mice. Infection with SARS-CoV-2 MA10 also results in increased pathogenicity in aged mice and therefore serves as a lethal mouse model for SARS-CoV-2 pathogenesis. The utility of SARS-CoV-2 MA and SARS-CoV-2 MA10 for screening potential treatments has been demonstrated, through vaccine challenge studies and testing of therapeutic candidates.
- Captures multiple aspects of SARS-CoV-2 pathogenesis in young and aged immune competent mice.
- Provides a high-throughput in vivo system to evaluate potential treatments.
Name: Matthew Howe