Abstract COVID-19, caused by the coronavirus SARS-CoV-2, has an unpredictable clinical course ranging from an asymptomatic carrier state to severe acute respiratory syndrome (SARS). The vast majority of young individuals have an asymptomatic to moderate clinical course, but a subset of patients develop a severe systemic inflammatory response. The genetic factors regulating the immune response to SARS-CoV-2 remain undefined. Our preliminary data shows that since Boston Children’s Hospital began admitting patients with COVID- 19 in late March 2020, eight of nine of patients with severe COVID-19 had pre-existing lymphopenia, autoimmunity, or hypogammaglobulinemia. None of four patients with moderate COVID-19 had prior history of immune dysfunction. Whole exome sequencing on one of the patients with severe COVID-19 and extremely elevated soluble CD25 levels identified a heterozygous frameshift mutation (p.Ala9Profs) in SOCS1, encoding Suppressor of Cytokine Signaling 1. The mutation is predicted to result in SOCS1 haploinsufficiency, which results in overactivation of T cells in SOCS1 haploinsufficient mouse models. SARS-CoV-2 may induce endoplasmic reticulum (ER) stress through multiple pathways. Several viral proteins bind to ER resident proteins and to COPI, the heptameric complex that mediates retrograde protein trafficking from the Golgi to the ER, potentially causing ER stress. Massive cytokine secretion induces ER stress by increasing the load of nascent proteins in the ER, and cellular exposure to high levels of circulating cytokines further increases ER stress. Notably, the clinical phenotype of severe COVID-19 parallels that observed in COPG1 mutant mice during polymicrobial infection, resulting in increased ER stress in activated lymphocytes. We hypothesize that young individuals with severe COVID-19 exhibit a dysregulated immune response to SARS-CoV-2 infection, characterized by increased ER stress and reduced lymphocyte survival. In AIM I we will test the hypothesis that children with severe COVID-19 have deleterious variants in genes regulating the equilibrium between anti-viral immunity and immune homeostasis. In AIM II we will test the hypothesis that ER stress contributes to the T cell lymphopenia characteristic of severe COVID-19 and can be reversed with administration of TUDCA. The proposed studies have the potential for identification of genetic variants underlying severe COVID-19, and thereby pathways important for disease severity. In parallel, our investigations of ER stress in immune cells from patients with COVID-19 will test the hypothesis that readily available ER stress relieving agents may be useful for the treatment of COVID-19.