There is significant disease heterogeneity among mouse strains infected with the helminth Schistosoma mansoni . Here, we uncover a unique balance in two critical innate pathways governing the severity of disease. In the low-pathology setting, parasite egg-stimulated dendritic cells (DCs) induce robust interferon (IFN)β production, which is dependent on the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) cytosolic DNA sensing pathway and results in a Th2 response with suppression of proinflammatory cytokine production and Th17 cell activation. IFNβ induces signal transducer and activator of transcription (STAT)1, which suppresses CD209a, a C-type lectin receptor associated with severe disease. In contrast, in the high-pathology setting, enhanced DC expression of the pore-forming protein gasdermin D (Gsdmd) results in reduced expression of cGAS/STING, impaired IFNβ, and enhanced pyroptosis. Our findings demonstrate that cGAS/STING signaling represents a unique mechanism inducing protective type I IFN, which is counteracted by Gsdmd.

Infection with the helminth parasite Schistosoma mansoni causes morbidity and mortality via a pathogenic host CD4 T cell-mediated immune response directed against parasite egg antigens. We now demonstrate that stimulation of dendritic cells (DCs) with schistosome eggs induces robust IFNβ production in a manner dependent on the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon genes (STING) cytosolic DNA sensing pathway, resulting in the suppression of proinflammatory IL-1β and IL-23 production and in Th17 cell activation. Consistent with these results, low-pathology BL/6 mice lacking STING exhibited markedly enhanced hepatic granulomatous inflammation associated with significantly increased Th17 and diminished Th2 cytokine responses. Mechanistically, IFNβ acts by suppressing DC expression and function of CD209a, a C-type lectin receptor associated with severe schistosome immunopathology. Importantly, there was an increased baseline CD209a expression in unstimulated DCs from STING−/− mice, suggesting a role for constitutive IFN signaling. Our findings demonstrate that innate, cGAS/STING-dependent sensing of parasite DNA represents a novel pathway inducing type I IFN production, which protects the host from excessive inflammation and immunopathology in schistosomiasis. This work is supported by NIAID grant R01 AI018919 to MJS.