Abstract
Schistosomiasis is a human parasitic disease responsible for serious consequences for public health, as well as severe socioeconomic impacts in developing countries. Here, we provide evidence that the adaptor molecule STING plays an important role in Schistosoma mansoni infection. S. mansoni DNA is sensed by cGAS leading to STING activation in murine embryonic fibroblasts (MEFs). Sting−/− and C57BL/6 (WT) mice were infected with schistosome cercariae in order to assess parasite burden and liver pathology. Sting−/− mice showed worm burden reduction but no change in the number of eggs or granuloma numbers and area when compared to WT animals. Immunologically, a significant increase in IFN-γ production by the spleen cells was observed in Sting−/− animals. Surprisingly, Sting−/− mice presented an elevated percentage of neutrophils in lungs, bronchoalveolar lavage, and spleens. Moreover, Sting−/− neutrophils exhibited increased survival rate, but similar ability to kill schistosomula in vitro when stimulated with IFN-γ when compared to WT cells. Finally, microbiota composition was altered in Sting−/− mice, revealing a more inflammatory profile when compared to WT animals. In conclusion, this study demonstrates that STING signaling pathway is important for S. mansoni DNA sensing and the lack of this adaptor molecule leads to enhanced resistance to infection.
Highlights
Schistosomiasis is a neglected tropical disease caused by parasites of the genus Schistosoma[1]
In order to evaluate whether the Stimulator of Interferon Genes (STING) signaling pathway is able to recognize S. mansoni DNA, C57BL/6 (WT) murine embryonic fibroblasts (MEFs) were transfected with the parasite DNA or dsDNA90 for 6 hours
When MEFs were transfected with S. mansoni DNA or dsDNA90, STING migrated from the cytoplasm to the perinuclear region of these cells, forming punctual aggregates (Fig. 1a)
Summary
Schistosomiasis is a neglected tropical disease caused by parasites of the genus Schistosoma[1]. The three major species infective to humans are Schistosoma mansoni, S. japonicum, and S. haematobium It is considered the most prevalent neglected disease worldwide, after malaria[2]. CGAS detects cytosolic dsDNA through its binding to the sugar-phosphate backbone, regardless of the sequence[9] This recognition promotes dimerization and the activation of cGAS, allowing ATP and GTP to access its catalytic cavity leading the synthesis of the second messenger cyclic GMP-AMP (2’3′-cGAMP)[12,13]. S. mansoni larvae and adult worms migration in host tissues might induce cellular damage, leading to release of both endogenous and parasite DNA. This study demonstrated for the first time that S. mansoni DNA is sensed by the cGAS/STING axis and lack of this signaling pathway renders mice more resistant to infection. Understanding the mechanisms involved in establishing schistosome infection may provide new approaches for therapeutic and prophylactic interventions
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