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

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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.