Mechanistic characterization of SARS-CoV2 associated kidney injury

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SARS-CoV2 is a highly contagious, novel human coronavirus that causes coronavirus disease 2019 (COVID- 19). Currently over 16.5 million people in the US have confirmed infection with SARS-CoV2 and over 300,000 have died. Severe COVID-19 is characterized by pulmonary and systemic inflammation and multi-organ dysfunction, with a significant portion of severe COVID patients developing acute kidney injury. 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 a predictor of severe COVID-19 disease. The mechanism by which the host restricts necroptosis is unclear. In 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. We have also shown that ISG15 deficient mice rapidly succumb to ischemia-reperfusion injury of the kidney characterized by a massive release of proinflammatory cytokines. In this proposal we will test the hypothesis that ISG15 serves as a critical host restriction factor in regulating programmed necroptosis and downstream inflammatory responses within the kidney to limit acute kidney injury during SARS-CoV2 infection. We will utilize kidney organoids derived from induce pluripotent stem cells in which ISG15 has been deleted by CRISPR, a co-culture system with kidney organoids and primary tracheal epithelial cultures (hTECs), and in vivo mouse model of SARS-CoV-2 to ask several questions including: 1) Does SARS- CoV2 induce damage to kidney epithelial cells via direct viral transduction or in response to systemic inflammation?; 2) Does ISG15 modulate necroptotic cell death as well as proinflammatory cytokine/chemokine production in kidney epithelial cells during SARS-CoV2 infection?; 3) Does necroptosis and its regulation by ISG15 contribute to acute kidney injury during SARS-CoV2 infection? Overall, our studies will provide important insight into host factors that restrict necroptosis and could be an important contributor to severe COVID-19 induced kidney injury.