The cellular and molecular basis for malaria parasite invasion of the human red blood cell

Abstract

Malaria is a major disease of humans caused by protozoan parasites from the genus Plasmodium. It has a complex life cycle; however, asexual parasite infection within the blood stream is responsible for all disease pathology. This stage is initiated when merozoites, the free invasive blood-stage form, invade circulating erythrocytes. Although invasion is rapid, it is the only time of the life cycle when the parasite is directly exposed to the host immune system. Significant effort has, therefore, focused on identifying the proteins involved and understanding the underlying mechanisms behind merozoite invasion into the protected niche inside the human erythrocyte.

Figure 1.

The life cycle of P. falciparum. The Anopheles mosquito bites a human and injects sporozoite forms. These move to the liver and invade hepatocytes, in which they develop to produce exoerythrocytic merozoite forms that are released into the blood stream. Merozoites invade erythrocytes and grow into trophozoites and mature schizonts. Merozoites are released that reinvade new erythrocytes. Gametocytes, formed from the asexual blood stage, are taken up by a feeding mosquito into the gut where they mature to form male and female gametes. The fertilized zygote develops to an ookinete and an oocyst and finally sporozoites that migrate to the salivary glands.

Figure 2.

Three-dimensional diagram of a merozoite and its core secretory organelles. (A) The sectioned cell highlights the major cellular architecture and organelle repertoire of the invasive merozoite, with dissected organelles listing core molecular constituents of these key invasion-related compartments. Of note, though definition of secretory organelles is limited to dense granules, micronemes, and rhoptries, there is mounting evidence that subpopulations of organelles and subcompartmentalization within organelles (specifically the rhoptries) certainly exist. The rhoptries are divided into three segments, with PfRh1, -2a, -2b, -4, and -5 in the most distal segment and RON2-5 in the next segment. This organization is predicted based on functionality and early release of the PfRh proteins onto the merozoite surface during invasion as opposed to the release of the RON protein complex, but it has not yet been demonstrated definitively (Riglar et al., 2011). The dense granules are released very soon after invasion and include components of a putative protein translocon that is inserted into the parasitophorous vacuole membrane. Ring-infected erythrocyte surface antigen (RESA) is released from dense granules and exported to the infected red blood cell. The body of the rhoptry bulb contains lipids and other proteins involved in forming the parasitophorous vacuole, including RAP1-3 and RAMA. (B) A P. falciparum merozoite in the process of invading a human red blood cell (image courtesy of S. Ralph, University of Melbourne, Melbourne, Australia). Bar, 200 nm.

Figure 3.

A time course of merozoite invasion of the erythrocyte from egress through postinvasion. (A) A cellular overview is given with associated timing of organelle secretion and key mechanistic or signaling steps listed below. After apical reorientation, the merozoite establishes a tight junction that is marked by RON4 and AMA1. The tight junction is ultimately connected to the actomyosin motor, although the exact nature of this has yet to be established. As the tight junction moves across the merozoite surface, proteins are shed into the supernatant through the activity of proteases such as ROM4, ROM1, SUB1, and SUB2. The parasitophorous vacuole and membrane are formed primarily from the rhoptries, although some red cell membrane components are included, which expel their contents, forming the space into which the parasite can move under the action of the actomyosin motor. Once the tight junction reaches the posterior end of the parasite, the membranes seal by an as yet unknown mechanism.