Signaling during Plasmodium falciparum merozoite invasion.

Malaria remains a huge global health burden, affecting hundreds of millions of people each year.While progress has been made in controlling the disease in some parts of the world significantchallenges remain. Of particular concern is the appearance of parasite resistance to artemesininhighlighting the urgent need for new effective drugs. Currently most antimalarial drugs targetprocesses during the maturation of the parasite in the erythrocyte with no drug targeting the merozoiteor merozoite invasion. Recent work showed that in Plasmodium falciparum Calcium-signaling in themerozoite are important during invasion while studies carried out mainly in the 1980’s have indicatedthat specific phosphorylation of erythrocyte proteins are important for invasion. Neither merozoitesignaling nor the signaling events that lead to phosphorylation of erythrocyte proteins are understoodin any detail though they could potentially serve as a new set of targets against the blood stage of theparasite. In the proposal here we aim to gain more insight into the different signaling steps that occurboth in the merozoite as well as the host erythrocyte early on during the invasion process. Using arange of inhibitors that arrest merozoites at different stages of the invasion process along with uniquefluorescent sensor molecules we aim to study changes in Ca2+, Na+, K+ and pH in both the merozoiteas well as erythrocyte during the invasion. In addition, we will complement these studies with adetailed identification and analysis of the changes in the phosphorylation pattern of merozoite anderythrocyte proteins during invasion. Molecules identified to play a role in signaling will be studied inmore detail to understand their mode of action. Together this will provide us a first glimpse of thesignaling mechanisms important in merozoite invasion and how these processes might be a newtarget for malaria intervention.