Meiosis in Plasmodium: How does it work?

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The main goal of this research is to understand how reversible protein phosphorylation - a key process that switches proteins on and off - regulates sexual development of single-cell parasites belonging to the genus Plasmodium, which are the causative agent of malaria. These parasites have a complex life-cycle in mammalian hosts and the mosquito vector, and the sexual stages in the mosquito are responsible for transmission to the host. Of particular importance for this application, we have shown previously that the malaria parasite relies on two enzymes - a protein kinase called NEK4 and protein phosphatase called PPM2 - to drive an essential process in sexual reproduction called meiosis. Meiosis is an essential part of sexual reproduction that produces sex cells (e.g. sperm and egg cells) ready for fertilisation. Compared to model systems, such as humans, meiosis is highly different in the malaria parasite since it proceeds post-fertilisation in the developing zygote, a crucial stage required for transmission from the mosquito. NEK4 and PPM2 drive this process; however, the proteins they switch on and off are largely unknown, as are the functions of the proteins they target. Hence, identification of the proteins NEK4 and PPM2 regulate may uncover the key players that drive Plasmodium meiosis, and most importantly whether these could be targeted by drugs that will prevent malaria transmission. The sexual stages of the malaria parasite (i.e. meiosis stages) that infects humans are difficult to study experimentally, and therefore we will be using a rodent malaria parasite called Plasmodium berghei as a model that mimics the human parasite. Crucially, with P. berghei we can access and study the whole parasite life cycle, particularly the sexual stages in the mosquito. We also will utilise several state-of-the-art methods including proteomics, phosphoproteomics and cell biology techniques towards understanding how NEK4 and PPM2 control meiosis in the malaria parasite cell, and whether we can identify new proteins that drive its function. The main questions to be addressed are where and how these molecules work, what proteins do they target during meiosis and can we identify new functions for their targets? Overall, we aim to deliver fundamental knowledge of the meiotic processes that govern malaria development in the mosquito and potentially uncover novel therapeutic agents, and expect that the discoveries and new insights provided will be directly applicable to human malaria parasites.