Abstract
Malaria is caused by Plasmodium parasites, which invade and replicate in erythrocytes. For Plasmodium falciparum, the major cause of severe malaria in humans, a heterotrimeric complex comprised of the secreted parasite proteins, PfCyRPA, PfRIPR and PfRH5 is essential for erythrocyte invasion, mediated by the interaction between PfRH5 and erythrocyte receptor basigin (BSG). However, whilst CyRPA and RIPR are present in most Plasmodium species, RH5 is found only in the small Laverania subgenus. Existence of a complex analogous to PfRH5-PfCyRPA-PfRIPR targeting BSG, and involvement of CyRPA and RIPR in invasion, however, has not been addressed in non-Laverania parasites. Here, we establish that unlike P. falciparum, P. knowlesi and P. vivax do not universally require BSG as a host cell invasion receptor. Although we show that both PkCyRPA and PkRIPR are essential for successful invasion of erythrocytes by P. knowlesi parasites in vitro, neither protein forms a complex with each other or with an RH5-like molecule. Instead, PkRIPR is part of a different trimeric protein complex whereas PkCyRPA appears to function without other parasite binding partners. It therefore appears that in the absence of RH5, outside of the Laverania subgenus, RIPR and CyRPA have different, independent functions crucial for parasite survival.
Highlights
Malaria, caused by Plasmodium parasites, remains a major world health problem with 219 million annual malaria cases and 435,000 deaths reported in 2017 [1]
Initial weak surface interactions between the merozoite and erythrocyte [5] precede strong deformations of the erythrocyte caused by erythrocyte bindinglike (EBL) and reticulocyte binding-like (RBL) ligands released from apical organelles onto the merozoite surface, binding to their specific host cell receptors
Using CRISPR/Cas9 gene editing paired with DiCre recombinase methodology to generated inducible gene deletions, we demonstrate here that both Pkcyrpa and Pkripr are essential for P. knowlesi survival in vitro and are involved in the erythrocyte invasion process
Summary
Malaria, caused by Plasmodium parasites, remains a major world health problem with 219 million annual malaria cases and 435,000 deaths reported in 2017 [1]. P. knowlesi is primarily a macaque parasite, but zoonotic infection can cause death and severe disease in humans, with a significant number of cases in Southeast Asia [3] As part of their complex life cycle, Plasmodium parasites infect and replicate within erythrocytes to cause the clinical symptoms of malaria. Initial weak surface interactions between the merozoite and erythrocyte [5] precede strong deformations of the erythrocyte caused by erythrocyte bindinglike (EBL) and reticulocyte binding-like (RBL) ligands released from apical organelles (the micronemes and rhoptry neck, respectively) onto the merozoite surface, binding to their specific host cell receptors These interactions appear to mediate the merozoite reorientation, which is followed by the release of the rhoptries and moving junction formation between the parasite and the erythrocyte. The invasion process is completed with the sealing of the parasitophorous vacuole (PV) and erythrocyte plasma membrane
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