Proteases in egress of the malaria parasite from its host red blood cell. (360G-Wellcome-086550_Z_08_Z)

Approximately 40% of the world s population is at risk from malaria, and with the increasing prevalence of drug resistance, the need for novel, effective drugs against this pathogen is increasingly urgent. The most virulent form of malaria is caused by waves of replication of the unicellular parasite Plasmodium falciparum within an intraerythrocytic parasitophorous vacuole (PV). At 48-hour intervals, rupture of the infected erythrocyte releases merozoites (a process called egress) which invade f resh erythrocytes to repeat the cycle. Egress is governed by the release of an essential parasite serine protease called SUB1 from maturing merozoites into the PV space. SUB1 initiates a cascade which involves the proteolytic processing of a papain-like enzyme family called SERA. At least two members of this family, SERA5 and SERA6, are essential for parasite viability. SERA5, and likely the other SERAs, is then further processed by another, as yet unidentified protease (which we refer to as the P50C protease). The purpose of this project is to investigate the role of the SERA proteins in parasite egress; verification of the enzymatic activity of the SERAs and identification of their substrates and of the P50C protease will provide new targets for the development of antimalarial drugs.