Epigenetic control of gene expression in malaria gametocytes during transmission from the human to the mosquito

疟疾寄生虫恶性疟原虫从人到蚊子的传播是这种寄生虫生命周期中的主要瓶颈，并且是由性前体细胞（配子母细胞）介导的。配子体在人类红细胞中成熟大约10天，然后被吸血按蚊吸收。在与血粉一起进入蚊子中肠后，配子母细胞被各种环境刺激激活。大约20%的疟原虫基因在配子母细胞中特异性表达，在激活过程中，不同的基因库被打开，这些激活诱导的分子变化不仅启动配子发生，而且为寄生虫在昆虫载体中的生活周期进展做好准备。由于配子母细胞是唯一能够在蚊子中建立感染的寄生虫阶段，它们在疟疾的传播中发挥着关键作用，是阻断传播干预措施的主要目标。该建议旨在更好地了解参与人类宿主配子体发育调控和寄生虫向蚊子媒介传播的关键因素。我们将通过分析整个配子体发育和配子体激活过程中组蛋白的修饰来研究表观遗传学的作用（目的1）。同时，我们将使用DNA微阵列分析来表征mRNA转录谱（目的2）。我们的研究结果将揭示配子母细胞的关键调节因子，并将识别对蚊子中肠阶段的有性生殖和进一步发展重要的疟原虫蛋白，从而深入了解疟原虫快速适应昆虫宿主的遗传基础。

The transmission of the malaria parasite Plasmodium falciparum from the human to the mosquito represents a major bottleneck in the life-cycle of this parasite and is mediated by sexual precursor cells, the gametocytes. Gametocytes mature in the human red blood cell during a period of approximately 10 days and are then taken up by the blood-feeding Anopheles mosquito. Upon entering the mosquito midgut with the blood meal, gametocytes become activated by various environmental stimuli. Approximately 20% of the plasmodial genes are specifically expressed in the gametocytes, and during activation, a different repertoire of genes is switched on. These activation-induced molecular changes not only initiate gametogenesis, but also prepare the parasites for life-cycle progression in the insect vector. Because gametocytes are the only parasite stages capable of establishing an infection in the mosquito, they play a crucial role in the spread of malaria and represent prime targets for transmission blocking interventions. This proposal aims to gain a better understanding of the critical elements involved in the regulation of gametocyte development in the human host and in parasite transmission to the mosquito vector. We will investigate the role of epigenetics by analysing histone modifications throughout gametocyte development and during activation of the gametocytes (aim 1). In parallel, we will characterize mRNA transcript profiles using DNA microarray analyses (aim 2). Our findings will reveal key regulators of gametocytes and will identify plasmodial proteins important for sexual reproduction and further development of the mosquito midgut stages, thereby providing insights into the genetic basis of the rapid adaption of Plasmodium to the insect host.