SARS-CoV2 is a highly contagious, novel human coronavirus that causes coronavirus disease 2019 (COVID-19). Currently over 7.4 million people in the US have confirmed infection with SARS-CoV2 and over 215,000 have died. Severe COVID-19 is characterized by pulmonary and systemic inflammation and multi-organ dysfunction, which disproportionally affects elderly patients. The mechanism by which SARS-CoV2 triggers such severe pathogenesis is poorly understood. Recent clinical studies have suggested that cell death, especially the induction of necroptosis, may be predictor of severe COVID-19 disease. The mechanism by which the host restricts necroptosis is unclear. In the preliminary data we have shown that the interferon induced protein, ISG15, acts as a negative regulator of necroptosis and its downstream inflammatory responses during viral infection. In this proposal we will test the hypothesis that SARS-CoV2 induces necroptosis and that ISG15 functions as a negative regulator of necroptosis in respiratory epithelial cells. We will use in vitro primary tracheal epithelial cultures (hTECs) and an in vivo mouse adapted SARS-CoV2 animal model to ask several questions including: 1) Does SARS- CoV2 induce necroptosis in respiratory epithelial cells; 2) Does ISG15 modulate necroptotic cell death as well as proinflammatory cytokine/chemokine production in respiratory epithelial cells during SARS-CoV2 infection?; 3) Does necroptosis and its regulation by ISG15 contribute to SARS-CoV2 pathogenesis? Overall, our studies will provide important insight into the pathogenesis of SARS-CoV2 infection and provide potential insight into mechanisms underlying severe disease, which may direct efforts toward the development of diagnostic markers and future countermeasures.

SARS-CoV-2 is a highly contagious, novel human coronavirus that causes coronavirus disease 2019 (COVID-19) which has resulted in severe morbidity and mortality. It remains unclear why certain populations, particularly the elderly, are more susceptible to severe COVID-19 symptoms. The goal of this work is to determine whether excessive inflammatory cell death, regulated by ISG15 and RIPK3, acts as a key factor in severe COVID-19 disease.