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

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一个主要瓶颈，由性前体细胞-配子体介导。配子体在人的红细胞中成熟大约10天，然后被食血的按蚊摄取。当蚊子带着血粉进入中肠后，配子体就会被各种环境刺激激活。大约20%的原虫基因在配子体中特异表达，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了配子发生，还为寄生虫在昆虫媒介中的生活史进程做好了准备。由于配子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，并且是传播阻断干预的主要目标。这项建议旨在更好地了解在人类宿主中调节配子体发育和寄生虫传播到蚊子媒介中所涉及的关键因素。我们将通过分析配子发育和配子激活过程中的组蛋白修饰来研究表观遗传学的作用(目标1)。同时，我们将使用DNA微阵列分析来鉴定信使核糖核酸转录谱(目标2)。我们的发现将揭示配子体的关键调控因素，并将识别对有性繁殖和蚊子中肠阶段的进一步发育至关重要的疟原虫蛋白质，从而为了解疟原虫快速适应昆虫宿主的遗传基础提供见解。

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.