STING-Dependent Pathways Restraining Severe Schistosome Immunopathology

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PROJECT SUMMARY Schistosomiasis is a major tropical parasitic disease caused by trematode worms of the genus Schistosoma. The etiopathology of schistosomiasis results from an inflammatory response to the tissue-trapped parasite eggs. Morbidity and mortality in infection with Schistosoma mansoni are due to a pathogenic CD4 T cell- mediated immune response against egg components, which results in granuloma formation and fibrosis in the liver and intestines. The spectrum of pathology ranges from mild gastrointestinal symptoms in most cases to severe hepatosplenomegaly, hemorrhage and death in a minority of patients. This variation also exists in mouse model of schistosomiasis where CBA mice develop severe egg induced immunopathology driven by IL-17-producing T cells (Th17 cells); while C57BL/6 (BL/6) mice develop milder lesions driven by Th2 cells. We propose to investigate a novel immune mechanism that protects the host from developing severe immunopathology. This is based on our observation that in BL/6 mice, the mild pathology is associated with a protective type I Interferon (IFN) response that is dependent on STING, an adaptor molecule that functions to detect the presence of cytosolic egg-derived DNA. Indeed, BL/6 mice deficient in STING, develop significantly larger hepatic lesions. The inhibitory effect of STING is via targeting CD209a, a C-type lectin receptor on APCs, which we recently reported to be associated with severe pathology. Based on these novel observations, we hypothesize that STING related pathways promote the development of antigen presenting cell (APC)s that contribute to reduced inflammation. Specific Aim 1 of the proposal is to define the role of the cGAS/STING pathway in suppressing egg-induced immunopathology. Specific Aim 2 is to elucidate how STING modulates CD209a expression. The proposed experiments represent a concerted effort to unravel novel innate immune mechanisms affording host protection in schistosomiasis, a heretofore unexplored area of research in this disease and other Th17 driven inflammatory diseases.