Human ISG15 and USP18 Deficiencies Underlying Type I Interferonopathies

Project Summary Type I interferons (IFN-Is) have well-documented potent antiviral and inflammatory properties. However, we and others have shown that the inflammatory effects of these cytokines can have detrimental effects on human health. Disorders caused by the prolonged effects of IFN-Is are collectively known as type I interferonopathies. Mendelian type I interferonopathies, such as Aicardi–Goutières syndrome (AGS) and spondyloenchondromatosis (SPENCD) are prime examples of severe neurologic, autoinflammatory and autoimmune diseases caused by the perpetual induction of IFN-Is. We have recently described more than 20 children presenting Mendelian type I interferonopathy. Genetically, we have shown these conditions to be due to complete or partial deficiencies of ISG15 or USP18. These deficiencies affect downregulation of the IFN-I response. Individuals with deficiencies of ISG15 or USP18 have high levels of IFN-I-stimulated gene products in their blood cells, high levels of resistance to viral infections, but also neurologic, autoinflammatory and autoimmune manifestations, akin to those of AGS and SPENCD. This proposal is built around the hypothesis that the pathogenesis of these deficiencies is driven by IFN-I responses in specific tissues, and that these responses could be harnessed in the development of new treatments. We plan to test this hypothesis by studying these deficiencies in vitro, ex vivo, and in vivo at the molecular, immunological, and tissue-specific levels, to determine their functional significance in IFN-I pathway regulation and resistance to viral infections in humans. Improvements in our understanding of the molecular regulation of IFN-I should shed light on the pathophysiology of these deficiencies, paving the way for the development of new treatments for managing persistent inflammatory disorders and enhancing antiviral responses.