Project Summary Many severe immune diseases in young patients with infection susceptibility and/or immune-mediated tissue damage are caused by a single-gene defect resulting in an inborn error of immunity. We have a long- standing interest in intensive investigation of severe immune diseases of childhood. Our approach is to pursue rigorous genetic and immunologic studies that define the genes, cell types, and pathways underlying pathology to glean clinically relevant insights into fundamental human biology directly from patients. Currently, the genetic, molecular, and cellular drivers of susceptibility and pathogenesis in rare cases of severe SARS-CoV2-related disease in young, otherwise healthy individuals are unknown. Defining these drivers will not only address the urgent health needs of children and teenagers afflicted with the recently surging ‘multisystem inflammatory syndrome in children’ (MIS-C) and severe respiratory manifestations associated with SARS-CoV2 infection but will also provide fundamental knowledge about immunopathology mechanisms that are a general feature of COVID-19 across the age spectrum. We have built an growing cohort of young COVID-19 patients and banked DNA, cells, and serum from saliva and peripheral blood samples to enable us to tackle this urgent crisis. Our preliminary data demonstrate feasibility to obtain suitable samples for multi-dimensional analysis of leukocytes from these patients and also raise testable hypotheses about the initiating and triggering events in MIS-C. Using primary human cells and cutting-edge technologies, two specific aims will be pursued. Aim 1) To define genetic susceptibility to severe COVID-19 in young, otherwise healthy subjects. Aim 2) To elucidate immune mechanisms mediating severe inflammatory responses in these children and teenagers. The results of these investigations will provide significant insights into COVID-19 genetics and inflammation and will lay the groundwork to help advance our understanding and treatment strategies for this world-wide pandemic.