Mechanisms of immune dysregulation in human PI3Kgamma deficiency

Project Summary Many severe immune diseases in young patients with infection susceptibility and/or immune-mediatedtissue 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 pursuerigorous genetic and immunologic studies that define the genes, cell types, and pathways underlying pathologyto 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-relateddisease in young, otherwise healthy individuals are unknown. Defining these drivers will not only address theurgent health needs of children and teenagers afflicted with the recently surging 'multisystem inflammatorysyndrome in children' (MIS-C) and severe respiratory manifestations associated with SARS-CoV2 infection butwill also provide fundamental knowledge about immunopathology mechanisms that are a general feature ofCOVID-19 across the age spectrum. We have built an growing cohort of young COVID-19 patients and bankedDNA, cells, and serum from saliva and peripheral blood samples to enable us to tackle this urgent crisis. Ourpreliminary data demonstrate feasibility to obtain suitable samples for multi-dimensional analysis of leukocytesfrom these patients and also raise testable hypotheses about the initiating and triggering events in MIS-C. Usingprimary human cells and cutting-edge technologies, two specific aims will be pursued. Aim 1) To define geneticsusceptibility to severe COVID-19 in young, otherwise healthy subjects. Aim 2) To elucidate immunemechanisms mediating severe inflammatory responses in these children and teenagers. The results of theseinvestigations will provide significant insights into COVID-19 genetics and inflammation and will lay thegroundwork to help advance our understanding and treatment strategies for this world-wide pandemic.