STING agonist protects against exacerbation of schistosome egg-induced immunopathology.

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 Th17 cell activation. 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 diABZI-3 in a high-pathology CBA mouse model. In vitro, diABZI-3 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. In vivo, a single dose of diABZI-3 administered to S. mansoni-infected CBA mice reduced liver and intestine granuloma size, lowered IL-1β, IL-17, and CD209a levels, promoted the Foxp3⁺ regulatory T cells, reduced Th17 recruitment, and mitigated inflammation-associated shifts in gut microbiota populations. Furthermore, blocking STING degradation with bafilomycin A1 sustained STING signaling, leading to pronounced IL-1β suppression. These findings highlight diABZI-3 as a promising therapeutic agent for reducing schistosome-induced immunopathology.