Genetic Analysis of COVID-19 Susceptibility and Resistance Determinants in the Collaborative Cross

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Abstract: The 2019 nCoV (SARS-CoV2 or nCoV2) is currently causing a global pandemic, and is on track to cause millions of infections, hundreds of thousands of deaths, and significantly disrupt healthcare systems and economies globally. nCoV2 is a group 2B coronavirus that is 75% identical to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), which emerged in 2003. Approximately 10% of nCoV2 infections result in COVID-19 pneumonia that progresses to acute respiratory distress syndrome (ARDS), while a significant fraction of other individuals are asymptomatic or develop mild disease. While age, gender, and underlying health conditions predispose individuals to severe disease/death, we have a poor understanding of the factors that drive disease outcome. This knowledge is essential for understanding the pathogenesis of COVID-19, and for developing and testing safe and effective nCoV vaccines and therapies. However, while patient studies can provide insights into the disease risk factors, mechanistic analysis of these factors will require robust animal models of COVID-19 disease. Unfortunately, nCoV does not replicate in standard laboratory mice, and a significant need exists for new animal models that reproduce human-like COVID-19 disease, including ARDS. Collaborative Cross (CC) mice vary significantly in their response to SARS-CoV, and we were able to take advantage of this variation both to develop new models SARS-CoV-induced disease, while also identifying host genetic factors that regulate disease outcome. Based on this experience, we propose take advantage of a new mouse adapted SARS-CoV2 virus (maCoV2), which was recently developed in the Baric laboratory, to screen a panel of CC mouse strains for susceptibility to maCoV2-induced disease. This work will accomplish two critical research objectives by: 1) developing critically needed mouse models of nCoV2-induced disease, and 2) identifying polymorphic host genes/pathways that regulate resistance or susceptibility to nCoV2-disease.