Human ISG15 and USP18 Deficiencies Underlying Type I Interferonopathies

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Project Summary Type I Interferons (IFNs) are cytokines with well-defined anti-viral activities. While beneficial effects of IFNs are well documented, it has become clear that IFNs also have profound detrimental effects to human health. Disorders where dysregulated IFNs cause pathology are collectively termed type I Interferonopathies. Mendelian type I Interferonopathy disorders like Aicardi–Goutières syndrome (AGS) and spondyloenchondromatosis (SPENCD) showcase how constitutive upregulation of IFN activity can lead to neurologic and autoimmune disease pathology. We have recently identified eleven children presenting with Mendelian type I Interferonopathy. Genetically, we discovered six children with complete ISG15 deficiency and five children with complete USP18 deficiency. These deficiencies are the first genetic defects affecting the negative regulation of the IFN response. ISG15 and USP18 deficient individuals present with elevated IFN stimulated genes in their blood cells, increased resistance to viral infections, but also with neurologic and autoimmune manifestations, similar to AGS and SPENCD. This proposal is built around the hypothesis that ISG15 and USP18 are the essential factors controlling responsiveness to and duration of type I IFN responses.  To address this hypothesis we propose to study these eleven rare patients in vitro, ex vivo, and in vivo at the molecular, immunological, and clinical levels to determine the functional significance of these genes in regulating IFN pathway and resistance to viral infections in humans. Deeper understanding of molecular regulation of IFN will allow us to better understand the pathophysiology behind these deficiencies and will lay the ground for development of medicines aiding management of persistent inflammatory disorders and/or increased anti-viral responses.