The Cellular and Molecular Interaction Between Erythrocytes and Plasmodium falciparum Merozoites

Abstract

Plasmodium falciparum is the most lethal human malaria parasite, partly due to its genetic variability and ability to use multiple invasion routes via its binding to host cell surface receptors. The parasite extensively modifies infected red blood cell architecture to promote its survival which leads to increased cell membrane rigidity, adhesiveness and permeability. Merozoites are initially released from infected hepatocytes and efficiently enter red blood cells in a well-orchestrated process that involves specific interactions between parasite ligands and erythrocyte receptors; symptoms of the disease occur during the life-cycle's blood stage due to capillary blockage and massive erythrocyte lysis. Several studies have focused on elucidating molecular merozoite/erythrocyte interactions and host cell modifications; however, further in-depth analysis is required for understanding the parasite's biology and thus provide the fundamental tools for developing prophylactic or therapeutic alternatives to mitigate or eliminate Plasmodium falciparum-related malaria. This review focuses on the cellular and molecular events during Plasmodium falciparum merozoite invasion of red blood cells and the alterations that occur in an erythrocyte once it has become infected.

Keywords: host–parasite interaction; invasion; malaria; merozoite; pathogenesis; remodelling.

Figure 1

P. falciparum lifecycle. (A) P. falciparum Spz inoculation into a human host by a female Anopheles mosquito. (B) Spz entry to hepatocytes, Spz maturation into schizonts and Mrz release. (C) Mrz entry into RBCs. (D) Asexual multiplication within RBCs. (E) Some parasites differentiate to sexual stages; gametocytes are ingested by an Anopheles mosquito during a blood meal. (F) Sporogonic cycle. (G) Rosetting, sequestration and vascular occlusion.

Figure 2

P. falciparum Mrz invasion and major changes induced in infected RBC. (A) P. falciparum Mrz (B–G) parasite ligands and RBC receptors involved in initial contact, apical reorientation and tight junction formation during Mrz invasion of RBC. (H) P. falciparum ring stage growing inside the PVM, representing the interface between parasite and host cytoplasm. Maurer’s clefts are flat and elongated membrane vesicles; they are mobile in iRBC cytoplasm during early parasite stages. (I) P. falciparum trophozoite stage. Maurer’s clefts are attached to membrane skeleton during mature parasite stages. Tubovesicular network (TVN) extending from the PVM into iRBC cytoplasm. Caveola vesicle complex (CVC) containing P. falciparum antigens which could be involved in the transport and release of specific parasite antigens from the iRBC and in plasma protein uptake. J dots, K dots and exosomes are membrane structures that traffic some parasite proteins (e.g. PfEMP-1) through iRBC cytoplasm. Knobs covering the iRBC surface during late parasite stages. (J) P. falciparum cytoadherence mediated by the interaction between variant surface antigens and host receptors (K) P. falciparum schizont stage. (K) iRBC rupture and Mrz release. (L) Mrz release and RBC reinvasion.

Figure 3

RBC membrane. (A) uninfected RBC membrane with the ankyrin and 4.1R complexes linking the bilayer with the membrane skeleton. (B) Infected RBC membrane with anion channels, the exported parasite proteins PfEMP1, STEVOR and RIFIN, and the expressed adhesin KAHRP. These proteins interact with host receptors mediating cytoadherence to the human endothelial cells.