gms | German Medical Science

The infectious tropical disease malaria remains a major health problem in the world, resulting in 207 million new cases and approximately 627,000 deaths in 2012. Plasmodium parasites replicate in the human red blood cells for a period of weeks and months, but form sexual precursor cells, the intraerythrocytic gametocytes, upon receiving environmental signals, which then mediate the transmission of the parasite from the human host to the Anopheles mosquito. Gametocytes thus contribute to the spread of malaria and are therefore considered prime targets for transmission-blocking intervention strategies. Approximately 20% of the plasmodial genes are specifically expressed during gametocyte maturation and gametogenesis, which takes place in the mosquito midgut following the blood meal. In recent years, the importance of epigenetic control mechanisms during gene regulations was demonstrated for the blood stages of the human malaria parasite P. falciparum. An essential part of epigenetic control includes histone modifications on chromatin structures like histone methylation or acetylation, mediated by histone methyltransferases (HMTs), histone acetyltransferases (HATs) and histone deacetylases (HDACs). We here aimed to investigate the role of epigenetics for the gametocytes of P. falciparum during their maturation in the human blood and following their transmission to the mosquito. Semi-quantitative RT-PCR showed a partial down-regulation of some of the enzymes in gametocytes compared to trophozoites. Furthermore, to determine the effect of epigenetic control on gametocyte development and activation, inhibitors of histone-modifying enzymes (HMT: Bix-01294; HAT: AA, CPTH2; HDAC: TSA, SAHA) were tested by chemical loss-of-function studies. First analyses exhibited a strong effect of these inhibitors on gametocyte development and a moderate effect on gametogenesis. These studies imply that epigenetic control of gene expression by histone modifications like acetylation and methylation particularly play a role in gametocytogenesis. HMTs, HATs and HDACs of P. falciparum might represent promising targets for transmission-blocking drugs.