Functional dissection of Condensin and Cohesin in atypical mitosis and meiosis in Plasmodium

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Plasmodium is the causative agent of malaria and is responsible for about 584,000 human deaths annually, mostly children under the age of 5. The increasing resistance of the parasite to existing drugs and the lack of an efficient vaccine represent the main obstacles to combat this burden. Therefore, there is an urgent need for the development of innovative therapeutics. Plasmodium has a complex life cycle with diverse host environments, changes in cell shape, size and motility and an atypical mode of cell proliferation. The symptoms of the disease are manifest when malaria parasites invade host red blood cells, wherein the parasite divides and multiplies many times (endomitosis), eventually leading to destruction of the host cell. Some of the parasite cells may cease to divide and they become precursor sex cells (male and female gametocytes). When a female mosquito bites an infected person they ingest parasites along with the blood and this acts as a trigger to activate the precursor sex cells within the mosquito gut. The male gametocytes undergo rapid cell division (endoreduplication) to produce eight male gametes, which then fertilise the female gametes and the parasite life cycle continues in the mosquito gut. After further development and multiplication the parasite moves to the mosquito's salivary glands and is passed again to a new human host when the mosquito feeds.The process of Plasmodium cell division in host red blood cells, and during sexual development in the mosquito vector is very different, but both are essential for parasite growth and transmission. If any of these stages are blocked then both proliferation and transmission are curtailed. Therefore, it is critically important to understand how the parasite multiplies and divides at these stages so that we can devise ways to interfere with them by developing appropriate drugs. The molecules that control these types of atypical cell division in the parasite are very poorly understood. The project proposed here is to study the role of two important protein complexes: condensin and cohesin. Although these complexes are known to be involved in cell division in many model systems, there is no knowledge of how they function during malaria parasite cell division and proliferation. We can start by using the knowledge gathered in model systems and applying this to the malaria parasite. For example, we have recently identified one such protein (CDC20) in the malaria parasite and showed that it has a key role in regulating male gamete formation. In preliminary work showing that our approach is feasible, we have obtained evidence for the presence of condensin and cohesin in the parasite multiplying within the red blood cell, in the male sex cell and in the meiotic cell (an ookinete). Recent advances in analysing genes in malaria allow us to study the function of these molecules. For example, by taking away the gene, we can see what happens when the proteins are no longer made, and if they are tagged experimentally with a fluorescent marker we can see under the microscope where they are located in the parasite. We will also study how these molecules interact with other proteins during various processes such as chromosome segregation and cytokinesis, to name two. We can also purify these protein complexes and study their interactions using mass spectroscopy-based approaches. Therefore, we are now in a position where we can explore how cell division in malaria is controlled by these complexes and we can study how these molecules regulate different stages of cell division.Our study may identify molecular targets important in parasite cell division in host red blood cells and in the cells dividing within the mosquito vector. As a result, we may identify potential targets for drugs or vaccines that could in the future be used to block parasite replication in the blood and transmission from one individual to another through the mosquito.