Therapeutic targeting of necroptosis cell death pathways in COVID-19 ARDS: proof-of-principle

Abstract: SARS-CoV-2, which causes Coronavirus Disease 2019 (COVID-19), is the third highly pathogenic coronavirus that has led to significant global infections in humans. Acute respiratory distress syndrome (ARDS) is accompanied with alveolar epithelial and pulmonary capillary endothelial damage, myeloid cell influx and excessively high levels of circulating proinflammatory cytokines. Although the mechanisms of pathogenesis are unclear, data from work on SARS and ARD associated with sepsis point towards hyper-inflammation, activation of RIPK3-driven necroptosis and inflammasome-driven interleukin (IL)-1β/IL-18 cytokine production. Here we will investigate these processes in human endothelial and myeloid cells infected with SARS-CoV2 and test clinically-approved RIPK3 and inflammasome inhibitors in preventing necrotic cell death and release of inflammatory cytokines. In addition, examine the temporal profile of necrosis and necro-inflammation in patients with the severest form of COVID19.