Project: Plasmodium Escape from Protective Shells: Species- and Stage-Specific Functions of SERA Cysteine Proteases in Egress from Oocysts and Erythrocytes
During life cycle progression of malarial parasites, efficient and timely Plasmodium exit from replication-permissive compartments are central steps in parasite stage conversion. Strikingly, these protective shells are very diverse and comprise nucleated cells (hepatocytes), non-nucleated cells (erythrocytes) and cysts (mosquito oocysts). We have previously established that sporozoite egress is mediated by a papain-like cysteine protease, which is a member of a family of Plasmodium-specific serine repeat antigens (SERAs). We uncovered a synthetic rescue of an essential SERA by simultaneous deletion of SERA proteins with active site serine residues. This genocopy of the avian malarial parasite SERA repertoire offers an intriguing explanation for the expansion of the SERA gene family in mammalian Plasmodium parasites. In this project, we will employ experimental genetics approaches in both cultured Plasmodium falciparum parasites and the murine malaria model in an attempt to characterize the molecular mechanisms of the two essential SERA proteins, ECP1/PfSERA8 and PbSERA3/PfSERA6. The observed rare genetic interaction, synthetic viability, is indicative of previously unidentified mechanisms in protease/co-factor cross-talk to drive efficient and timely parasite exit. Mechanistic insights into protease-mediated escape of invasive Plasmodium stages from non-nucleated protective shells are also important for comparative analysis of the central roles of cysteine proteases in other parasitic and bacterial pathogens.