Research Projects

The Plasmodium aspartic proteases- Plasmepsins (PM) IX and X have recently been shown as druggable targets, with potent mode action on multiple life cycle stages. The reported mode of action of these inhibitors have been in blocking the maturase activity of both plasmepsins, that inturn effected key proteases like sUB1, AMA1 involved in invasion and egress. With such key role in parasite biology, it is obvious that PM IX and X are refractory to gene disruption, thus limiting their investigations in mosquito and liver stages of Plasmodium. While conditional KD approach facilitated to reiterate the roles of both PMs in invasion and egress, such investigations are only limited to asexual stages, and not feasible in mosquito and liver stages As the mechanism of parasite egress and invasion are conserved across the asexual blood and liver stages, a pertinent question that's worth exploring is whether PM IX and X have a role in sporozoite stages (to maintain their infectivity status), EEF development and egress from hepatocytes. To address this important lacunae, we propose to use a conditional mutagenesis system of yeast Flp/FRT system, to achieve editing of PM IX and X locus in Plasmodium mosquito stages, specifically at oocyst stages, by a Flp recombinase. This approach will allow studying the function of sporozoites (bearing PM IX and X edited locus) for their ability to infect, transform and egress from hepatocytes. These investigations will confirm if the same processing mechanism operate in pre-erythrocytic stages governed by PM IX and X, as occurs in asexual stages. such information shall broaden the therapeutic and curative approaches to curtail the parasite before onset of clinical malaria.