Authors

Discussion

Invasion of red blood cells (RBCs) by Plasmodium merozoites is a critical event in the life cycle of these parasites that ensures their continued survival within the host. Invasion progresses through several morphological steps, including gliding motility, deformation of the host RBC, a calcium ‘flux’ at the merozoite-RBC interface, and finally, parasite entry and resealing of the host cell. Throughout invasion, merozoites secrete numerous proteins from specialised secretory organelles, called micronemes and rhoptries, that facilitate each step.

One such ligand, Plasmodium falciparum Reticulocyte binding protein homolog 5 (PfRh5), is part of an essential pentameric complex hypothesised to mediate the calcium flux via an unknown mechanism. Importantly, just before, or during invasion itself, PfRh5 is proteolytically cleaved by the aspartic protease, Plasmepsin X (PMX), to release a short (~14 kDa) N-terminal pro-domain from the remainder of the protein. However, precisely when and why PMX processing occurs is not known.

Recently, we developed a Dimerisable Cre-Recombinase (DiCre) ‘conditional swap’ system to replace wild type PfRh5 with mutant copies upon rapamycin treatment¹, thus enabling us to investigate the functional importance of the PfRh5 pro-domain and PMX processing. We, as others have recently shown², demonstrate that the PfRh5 pro-domain is important for successful invasion, and that providing parasites with a pre-processed PfRh5 copy lacking a pro-domain does not complement the loss of full-length PfRh5. Finally, we show that parasites expressing a non PMX-cleavable version of PfRh5 also cannot invade, demonstrating that PMX processing is essential but needs to occur in a tightly ordered sequence of molecular events for invasion to proceed.

_{1 Farrell B et al. Structure of the PfRCR complex which bridges the malaria parasite and erythrocyte during invasion. Nature 2024; 625: 7995.}

_{2 Triglia T et al. Plasmepsin X activates the PCRCR complex of Plasmodium falciparum by processing PfRh5 for erythrocyte invasion. Nat Commun 2023; 14: 2219.}