The role of rhomboid proteases and a oocyst capsule protein in malaria pathogenesis and parasite development

Plasmodium, the etiological agent of malaria causes more than a million deaths mostly in children under the age of five, and nearly 500 million people suffer from this disease every year. The lack of an effective vaccine and the spread of resistance against currently used drugs underscores the need to identify new targets and approaches to control this disease. Plasmodium life cycle takes place in two hosts, namely, the vertebrate and the mosquito. The sexual stages of the parasite occur in the mosquito. This absolute dependence on the mosquito for parasite represents a potential weak link that could be exploited. A better understanding of parasite development in the mosquito may identify new targets for intervention.; In this work, I have attempted to address some of the questions pertaining to specific developmental events that take place during parasite development in the midgut. Soon after fertilization the motile ookinete that is formed inside the blood meal transforms into a sessile oocyst. The parasite then enlarges in size and a single oocyst can produce thousands of sporozoites, the infective forms. The factors that regulate oocyst differentiation are not well understood. This study identifies several novel genes that are expressed during oocyst development. During parasite development in the mosquito, a drastic reduction in number occurs as the parasite transforms from one stage to the other. However, once oocysts are formed they appear to be resistant against the mosquito defenses. In this study we identify an important function for a oocyst capsule protein in parasite survival in the mosquito.; Finally, this work also sheds light on the role of two rhomboid family serine proteases in parasite development and malaria pathogenesis. Overall, this study advances our understanding of Plasmodium development in the mosquito as well as in the vertebrate host and identifies potential targets for interfering with parasite transmission and malaria pathogenesis.