Uncovering Biomarkers for Chronic Toxoplasmosis Detection Highlights Alternative Pathways Shaping Parasite Dormancy
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PROVIDER: PRJNA1212153 | ENA |
REPOSITORIES: ENA
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Project description:Toxoplasma gondii, a protozoan parasite, causes toxoplasmosis, a widespread zoonotic and food-borne infection that poses significant risks, particularly in opportunistic and congenital cases. This obligate intracellular parasite is highly prevalent worldwide, largely due to its versatile life cycle, involving multiple hosts and transmission routes, and its ability to establish chronic infections. The presence of this neurotropic parasite in the brain poses a reactivation risk in immunocompromised individuals and might be associated with a higher likelihood of developing mental disorders. However, the role of the dormant bradyzoite stage in the pathophysiology of the disease is underexplored, mainly due to the lack of non-invasive detection methods and serologic tests targeting bradyzoite- or cyst-specific antigens. In this study, we performed an unbiased screening of the bradyzoite proteome and identified the Bradyzoite Serological Marker (BSM) as an additional serological biomarker, alongside the cyst-associated BCLA, to detect chronic stages in vivo. BSM and BCLA show high sensitivity and specificity in identifying cyst-bearing mice. However, in humans, these markers exhibit only moderate concordance, with a 30% positivity rate among individuals with prior immunity, suggesting variability in immune responses and complexities in diagnosing chronic toxoplasmosis. Importantly, bradyzoite serology helps differentiate recent from past infections by the teratogenic parasite Toxoplasma gondii, with BCLA improving the accuracy of pergestational infection diagnosis. Exploring the regulatory mechanisms controlling the expression of these markers revealed that the chromatin modifiers MORC and HDAC3 exert epistatic control over BFD1, a key regulator of bradyzoite development. While BFD1 governs a specific subset of bradyzoite markers, including BCLA, a sub-transcriptome comprising BSM relies on MORC/HDAC3 independently of BFD1. This complex gene regulation highlights the challenge in understanding Toxoplasma persistence, while offering new opportunities for improved serological diagnosis of congenital and chronic toxoplasmosis, particularly in individuals with mental health conditions or a risk of toxoplasmic reactivation.
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Project description:Infection-induced T cell responses must be properly tempered and terminated to prevent immuno-pathology. Using transgenic mice, we demonstrate that T cell intrinsic STAT1 signaling is required to curb inflammation during acute infection with Toxoplasma gondii. Specifically, we report that mice lacking STAT1 selectively in T cells expel parasites but ultimately succumb to lethal immuno-pathology characterized by aberrant Th1-type responses with reduced IL-10 and increased IL-13 production. We also find that, unlike STAT1, STAT3 is not required for induction of IL-10 or suppression of IL-13 during acute toxoplasmosis. Each of these findings was confirmed in vitro and ChIP-seq data mining showed that STAT1 and STAT3 co-localize at the Il10 locus, as well as loci encoding other transcription factors that regulate IL-10 production, most notably Maf and Irf4. These data advance basic understanding of how infection-induced T cell responses are managed to prevent immuno-pathology and provide specific insights on the anti-inflammatory properties of STAT1, highlighting its role in shaping the character of Th1-type responses.
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Project description:Toxoplasmosis is a major health issue worldwide especially for immune-deficient individuals and the offspring of newly infected mothers. It is caused by a unicellular intracellular parasite called Toxoplasma gondii. Although the drugs commonly used to treat toxoplasmosis are efficient, they present serious side effects and adverse events are common. Therefore, there is a need for the discovery of new compounds with potent anti-T. gondii activity. We have tested compounds designed to target enzymes that are involved in the epigenetic regulation of gene expression. Among the most active compounds, we identified a HDAC inhibitor that shows an IC50 of around 30 nM with a selectivity index of more than 100. MC1742 is active at inhibiting the growth of the parasite in vitro but also at preventing the consequences of the acute disease in vivo. This compound induces a hyper-acetylation of histones while acetylated tubulin level remains unchanged. After MC1742 treatment, the parasite expression profile is profoundly changed with the activation of genes preferentially expressed in the sexual stages that are normally repressed at the tachyzoite stage. These findings suggest that this compound disturbs the T. gondii gene expression program, inducing parasite death.
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