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Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.

ABSTRACT: Treatment and control of schistosomiasis relies on the only available drug, praziquantel, and the search for alternative chemotherapeutic agents is therefore urgent. Egg production is required for the transmission and immunopathology of schistosomiasis and females of S. mansoni lay 300 eggs daily. A large fraction of the total mRNA in the mature female worm encodes one eggshell protein, Smp14. We report that the nuclear receptors SmRXR1 and SmNR1 regulate Smp14 transcription through the recruitment of two histone acetyltransferases (HATs), SmGCN5 and SmCBP1. The treatment of HEK293 cells with histone deacetylase (HDAC) inhibitors (NaB or TSA) produced an 8-fold activation of the SmRXR1/SmNR1-mediated Smp14 promoter activity. Incubation with synthetic HAT inhibitors, including PU139, significantly impaired the Smp14 promoter activity in these cells. Worm pairs cultivated in the presence of PU139 exhibited limited expression of Smp14 mRNA and protein. ChIP analysis demonstrated chromatin condensation at the Smp14 promoter site in worms treated with PU139. ChIP also revealed the presence of H3K27me3 and the absence of RNA Pol II at the Smp14 promoter region in the PU139-treated worms. Most significantly, the PU139-mediated inhibition of Smp14 expression resulted in a significant number of abnormal eggs as well as defective eggs within the ootype. In addition, scanning electron microscopy revealed structural defects and unformed eggshells, and vitelline cell leakage was apparent. The dsRNAi-targeting of SmGCN5 or SmCBP1 significantly decreased Smp14 transcription and protein synthesis, which compromised the reproductive system of mature female worms, egg-laying and egg morphology. Our data strongly suggest that the inhibition of Smp14 expression targeting SmGCN5 and/or SmCBP1 represents a novel and effective strategy to control S. mansoni egg development.

SUBMITTER: Carneiro VC

PROVIDER: S-EPMC4014452 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.

Carneiro Vitor Coutinho VC de Abreu da Silva Isabel Caetano IC Torres Eduardo José Lopes EJ Caby Stephany S Lancelot Julien J Vanderstraete Mathieu M Furdas Silviya D SD Jung Manfred M Pierce Raymond J RJ Fantappié Marcelo Rosado MR

PLoS pathogens 20140508 5

Treatment and control of schistosomiasis relies on the only available drug, praziquantel, and the search for alternative chemotherapeutic agents is therefore urgent. Egg production is required for the transmission and immunopathology of schistosomiasis and females of S. mansoni lay 300 eggs daily. A large fraction of the total mRNA in the mature female worm encodes one eggshell protein, Smp14. We report that the nuclear receptors SmRXR1 and SmNR1 regulate Smp14 transcription through the recruitm ...[more]

PMID: 24809504

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Project description:BackgroundEpidemiological data from Zimbabwe suggests that genital infection with Schistosoma haematobium may increase the risk of HIV infection in young women. Therefore, the treatment of Schistosoma haematobium with praziquantel could be a potential strategy for reducing HIV infection. Here we assess the potential cost-effectiveness of praziquantel as a novel intervention strategy against HIV infection.MethodsWe developed a mathematical model of female genital schistosomiasis (FGS) and HIV infections in Zimbabwe that we fitted to cross-sectional data of FGS and HIV prevalence of 1999. We validated our epidemic projections using antenatal clinic data on HIV prevalence. We simulated annual praziquantel administration to school-age children. We then used these model predictions to perform a cost-effectiveness analysis of annual administration of praziquantel as a potential measure to reduce the burden of HIV in sub-Saharan Africa.FindingsWe showed that for a variation of efficacy between 30-70% of mass praziquantel administration for reducing the enhanced risk of HIV transmission per sexual act due to FGS, annual administration of praziquantel to school-age children in Zimbabwe could result in net savings of US$16-101 million compared with no mass treatment of schistosomiasis over a ten-year period. For a variation in efficacy between 30-70% of mass praziquantel administration for reducing the acquisition of FGS, annual administration of praziquantel to school-age children could result in net savings of US$36-92 million over a ten-year period.ConclusionsIn addition to reducing schistosomiasis burden, mass praziquantel administration may be a highly cost-effective way of reducing HIV infections in sub-Saharan Africa. Program costs per case of HIV averted are similar to, and under some conditions much better than, other interventions that are currently implemented in Africa to reduce HIV transmission. As a cost-saving strategy, mass praziquantel administration should be prioritized over other less cost-effective public health interventions.

Dataset Information

Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.

Publications

Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.

Similar Datasets

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