Molecular and cellular dissection of kinesin motors in Apicomplexa to reveal roles in parasite proliferation

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The purpose of this research is to discover how replication of intracellular parasites is driven at a molecular and cellular level. We will focus our studies on Apicomplexan parasites because they are pathogens that cause diseases that are medically and economically important. These include Babesia, Eimeria and Neospora - which affect domesticated livestock causing huge economic losses - and Plasmodia, which causes malaria in a variety of vertebrates including man and kills 584,000 humans worldwide. The life cycles of these parasites are complex and alternate between sexual and asexual replicative stages in distinct hosts. Their replicative and proliferative mechanisms are just beginning to be understood. By understanding how these parasites replicate, we hope to first, provide general insight into the mechanisms and evolution of cell replication. Secondly, we hope to uncover unique features of parasite specific replication because this knowledge promises to help in the development of novel anti-parasite drugs.In the same way as our bodies have a skeleton that provides us with support and strength, the cells of parasites have a skeleton - called the cytoskeleton - which also provides support and structure. The cytoskeleton is involved in many important aspects of the parasite life cycle, including cellular transport, architecture and replication. Studying the cytoskeleton is important both so we can understand how normal cells work and how the parasite cytoskeleton differs from the host cells that they infect. This knowledge can be used to specifically target the cytoskeleton of pathogenic organisms with drugs that kill these organisms and prevent disease.In particular, this project will focus on a part of the cytoskeleton called microtubules. These are long cylindrical structures that act like tracks along which molecular transport motors carry cellular cargo. The motors that we will study are called kinesins and there are many different types, all of which move along microtubules. In this project, we will be investigating kinesins thought to be important for cell replication. We want to know both how parasite kinesins use cellular fuel to move along microtubules during replication and in what cellular context they perform these roles.The work by the Birkbeck research team will involve studying the three-dimensional structure of the cytoskeleton, because knowing what the cytoskeleton looks like will contribute to our understanding of how it works in the parasites themselves. We will use a very powerful microscope - an electron microscope - to take pictures of individual cytoskeleton molecules and then use computational analysis to combine these pictures and calculate their three-dimensional shape. A very important aspect of the proposed project is that we will also study the function of kinesins in malaria parasites themselves, in collaboration with experts in parasite cell biology at the University of Nottingham. Unlike many other such disease-causing parasites, our collaborators at Nottingham work on a species of malaria parasite (called P. berghei) that can be studied at all stages of its complex life cycle that are involved in the pathogenesis and transmission of the infection. Along with the ease with which this parasite can be genetically manipulated, this means that the contributions of different kinesins to parasite cell replication can be tested systematically.Initial analysis suggests that the kinesins from parasites such as malaria are different compared to kinesins from other organisms, including livestock and humans. This means that we might be able to find drugs that can block parasite kinesins - and thereby parasite replication - and not human kinesins. Such drugs could be very promising for development as anti-parasite treatments. Studying the structure and function of the parasite kinesins will allow us to investigate this idea.