Role of the Non-canonical Inflammasome in SARS-CoV-2-mediated Pathology and Coagulopathy

OVERALL - ABSTRACT COVID-19 is a world-wide health problem caused by SARS-CoV-2 viral infection in the lung with long-term symptoms in at least one third of patients. Many COVID-19 patients suffer from silent or identified thrombi in major organs such as the lung and the brain and have increased occurrence of cardiac events. They also experience high levels of inflammatory cytokines collectively called cytokine storm. Combined, these reactions lead to organ damage and long- term sequelae of infection commonly termed Long-COVID. Our Program team will join forces to determine the host cell mechanisms underlying tissue damage in the lung and how SARS-CoV- 2 alters immune responses (Project 1), as well as in the brain and blood circulation (Project 2). Identification and targeting of host mechanisms that control the multi-organ inflammatory pathologies of COVID-19 will synergize with the targeting of cellular enzymes that control SARS- CoV-2 replication (Project 3). Together, our team will reveal and test novel therapeutic targets to collectively tame inflammation, neuroinflammation and thrombosis and to restrict viral replication. To achieve such a comprehensive overall goal, the three Projects by four Cores that will offer administration, biostatistical and bioinformatic support, animal models and purified viral strains, and relevant primary cell types with genetic manipulations to perform the planned experiments. Our Program will spearhead efforts to better understand the mechanisms of COVID-19 pathology in different organs and to identify novel drug targets to limit the severity of COVID-19 and the development of Long-COVID.