Pharmacological activation of STING agonists blocks schistosome egg-mediated pro-inflammatory cytokine production

Abstract

Abstract Infection with the helminth parasite Schistosoma mansonicauses morbidity and mortality via a pathogenic host CD4 T cell-mediated immune response directed against parasite egg antigens. Here we demonstrated that low-pathology BL/6 mice lacking Stimulator of Interferon genes (STING) exhibited markedly enhanced hepatic granulomatous inflammation associated with significantly increased Th17 and diminished Th2 cytokine responses. Additionally, CBA mice tend to have a severe form of liver granulomatous inflammation due to a profound decrease of type I Interferon production. Since CBA bone marrow-derived dendritic cells have lower expression of STING, we hypothesized that STING agonists such as diABZI-3 and DMXAA would control the pro-inflammatory cytokine production and inflammation by activating STING expression and activation. Both diABZI-3 and DMXAA induced robust Interferon (IFN)β production, while IL-1β and IL-17 induced by schistosome eggs were impaired in egg-stimulated BMDCs. Our study suggest that STING agonists may serve as a novel therapeutic strategy to restrain schistosome immunopathology. This work is supported by NIAID grant R01 AI148656 to PK. This work is supported by NIAID grant R01 AI148656 to PK.