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Anti-Toxoplasma gondii effect of vorinostat in vitro and in vivo

ABSTRACT: Toxoplasma gondii is an important pathogenic protozoon that infects up to one-third of the world's population. In immunocompetent individuals, the infection generally is asymptomatic. However, in immunocompromised patients, the infection can lead to severe and fatal complications. This is due to the conversion of bradyzoites to tachyzoites as a result of reduced immune pressure. Therefore, it is necessary to discover drugs that have anti-Toxoplasma effect while simultaneously being effective against cancer.Our findings suggest that vorinostat demonstrates potency against T. gondii both in vitro and in vivo, which offers promise for treatment of human toxoplasmosis in cancer patients.

ORGANISM(S): Toxoplasma Gondii Rh-88

SUBMITTER: Chunxue Zhou

PROVIDER: PXD053997 | iProX | Wed Jul 17 00:00:00 BST 2024

REPOSITORIES: iProX

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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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Anti-Toxoplasma gondii effect of vorinostat in vitro and in vivo

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