Biochemistry and Pharmacology - Theses
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ItemDissecting the molecular basis of malaria parasite movement and host cell traversal in the mosquito midgut( 2015)Understanding the processes by which vector-borne pathogens colonise their invertebrate host is a fundamental question both in terms of the co-evolutionary biology of host-pathogen interactions and in dissecting the molecular basis of disease transmission. For the malaria parasites in particular, from the genus Plasmodium, the process by which the parasite targets and traverses the mosquito midgut epithelium is a critical bottleneck in lifecycle progression. Motility is a fundamental part of cellular life and survival for Plasmodium parasites. The motile life cycle forms achieve motility, called gliding, via the activity of an internal actomyosin motor. Although gliding is based on the well-studied system of actin and myosin, its core biomechanics are not completely understood. Although decades of research have revealed several key molecules involved in parasite traversal there is still little real understanding of the stepwise events that govern the journey of a parasite from the blood bolus to its destination under the basal lamina of the midgut. Despite the recent gains in reducing the burden of malaria disease in human populations there is still a pressing need to generate new therapeutics and strategies targeting this global pathogen. It has been recognised that any successful programme aiming towards disease eradication or elimination cannot rely on preventative and therapeutic treatments alone, but must also incorporate strategies to block parasite transmission through the mosquito vector. Much of the current literature surrounding Plasmodium transmission focuses on other lifecycle stages, neglecting the insect stage ookinete, which in itself presents a natural lifecycle bottleneck during progression through the mosquito midgut. Our findings suggest that ookinetes require dynamic actin in order to move and that this movement occurs in a left-handed helical fashion due to parasite shape. Extending our knowledge of key traversal proteins and their function, work on the vaccine candidate Cell Traversal protein for Ookinetes and Sporozoites, show that this protein is secreted in a Calcium stimulated, cGMP dependent protein kinase supported manner. Taken together, this body of work sheds light into the major interactions between the parasite and the mosquito in order to help support the broader goal to identify targets for transmission- blocking vaccine therapies against malaria disease.