Pharmacological Activation of STING attenuates the severity of schistosome immunopathology 2251618

Abstract Introduction Schistosomiasis, caused by parasitic worms, affects over 250 million people globally, with limited treatment options due to praziquantel’s inability to prevent reinfection or reduce immunopathology. In Schistosoma mansoni (S. mansoni) infection, egg-induced granulomatous inflammation in the liver and intestines is driven by CD4 T helper (Th) cell responses, with severe pathology in some individuals mediated by proinflammatory Th17 cells. We previously demonstrated that the stimulator of interferon genes (STING) mitigates schistosome egg-induced immunopathology by promoting type I interferon (IFN-I) production and suppressing Th17 responses. Here, we investigate the therapeutic potential of the STING agonist diABZI3 in a high-pathology CBA mouse model. Methods In vitro, diABZI3 pretreatment of bone marrow-derived dendritic cells (BMDCs) significantly enhanced IFNβ production while abolishing IL-1β and IL-17 expression in response to schistosome egg stimulation, an effect dependent on early administration. Results In vivo, a single dose of diABZI3 administered to S. mansoni-infected CBA mice reduced liver and intestine granuloma size, as well as IL-1β and CD209a levels, but induced the recruitment of Foxp3+ regulatory T cells. Furthermore, blocking STING degradation with bafilomycin A1 sustained STING signaling, leading to pronounced IL-1β suppression. Conclusion These findings highlight diABZI3 as a promising therapeutic agent for reducing schistosome-induced immunopathology and underscore the importance of early STING activation to modulate proinflammatory responses. Strategies to stabilize STING signaling may enhance therapeutic efficacy, though careful consideration of sustained activation is needed to avoid proinflammatory consequences. Funding Source NIAID grant R01 AI148656 to P.K. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)