The 21st century has recorded the emergence of three highly pathogenic respiratory coronaviruses, including Severe Acute Respiratory Coronavirus (SARS-CoV) in 2003, the ongoing Middle East Respiratory Coronavirus (MERS-CoV) in 2013 and a novel SARS-like coronaviruses SARS-CoV2 (SARS2) in Wuhan, China in Dec 2019. SARS2 causes COVID19, a severe acute respiratory distress syndrome (ARDS) and has infected 95000 individuals with ~20% severe cases and a ~3% mortality rate, resulting in over 3700 deaths. In the elderly, mortality rates approach 15%. The overall program goals are to identify the viral and host determinants, which regulate the atomic-level interactions between the SARS2 S-glycoprotein and various ACE2 receptor and associated entry components such as cellular proteases. The impact of these studies are high, as these interactions regulate 2019-nHCoV species specificity and host tropism, which play critical roles in viral pathogenesis and inform the evolutionary pathways leading to virus emergence and spread in humans and perhaps other intermediate hosts. In parallel, we apply these and other findings to developing robust mouse models of SARS2-mediated human disease, which is critical for not only evaluating viral pathogenesis but also for future testing of antiviral drugs, immunotherapeutics and vaccines.

The proposal studies the mechanisms by which the SARS-like clade 1 SARS2 epidemic and zoonotic precursor strains use novel interaction networks to regulate cross species transmission and pathogenesis in mammals. The proposal develops novel reagents and animal models that support the global effort to control the spread and severity of COVID-19 disease.