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The balance between gasdermin D and STING signaling shapes the severity of schistosome immunopathology.

ABSTRACT: 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.

SUBMITTER: Kalantari P

PROVIDER: S-EPMC10068786 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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The balance between gasdermin D and STING signaling shapes the severity of schistosome immunopathology.

Kalantari Parisa P Shecter Ilana I Hopkins Jacob J Pilotta Gois Andrea A Morales Yoelkys Y Harandi Bijan F BF Sharma Shruti S Stadecker Miguel J MJ

Proceedings of the National Academy of Sciences of the United States of America 20230321 13

There is significant disease heterogeneity among mouse strains infected with the helminth <i>Schistosoma mansoni</i>. 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 ...[more]

PMID: 36943884

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Project description:BackgroundThe role of pathogen genotype in determining disease severity and immunopathology has been studied intensively in microbial pathogens including bacteria, fungi, protozoa, and viruses, but is poorly understood in parasitic helminths. The medically important blood fluke Schistosoma mansoni is an excellent model system to study the impact of helminth genetic variation on immunopathology. Our laboratory has demonstrated that laboratory schistosome populations differ in sporocyst growth and cercarial production in the intermediate snail host and worm establishment and fecundity in the vertebrate host. Here, we (i) investigate the hypothesis that schistosome genotype plays a significant role in immunopathology and related parasite life history traits in the vertebrate mouse host and (ii) quantify the relative impact of parasite and host genetics on infection outcomes.MethodsWe infected BALB/c and C57BL/6 mice with four different laboratory schistosome populations from Africa and the Americas. We quantified disease progression in the vertebrate host by measuring body weight and complete blood count (CBC) with differential over an infection period of 12 weeks. On sacrifice, we assessed parasitological (egg and worm counts, fecundity), immunopathological (organ measurements and histopathology), and immunological (CBC with differential and cytokine profiles) characteristics to determine the impact of parasite and host genetics.ResultsWe found significant variation between parasite populations in worm numbers, fecundity, liver and intestine egg counts, liver and spleen weight, and fibrotic area, but not in granuloma size. Variation in organ weight was explained by egg burden and by intrinsic parasite factors independent of egg burden. We found significant variation between infected mouse lines in cytokines (IFN-γ, TNF-α), eosinophil, lymphocyte, and monocyte counts.ConclusionsThis study showed that both parasite and host genotype impact the outcome of infection. While host genotype explains most of the variation in immunological traits, parasite genotype explains most of the variation in parasitological traits, and both host and parasite genotype impact immunopathology outcomes.

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The balance between gasdermin D and STING signaling shapes the severity of schistosome immunopathology.

Publications

The balance between gasdermin D and STING signaling shapes the severity of schistosome immunopathology.

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