Host-parasite interactions that guide red blood cell invasion by malaria parasites

Abstract

Purpose of review: Malaria is caused by the infection and proliferation of parasites from the genus Plasmodium in red blood cells (RBCs). A free Plasmodium parasite, or merozoite, released from an infected RBC must invade another RBC host cell to sustain a blood-stage infection. Here, we review recent advances on RBC invasion by Plasmodium merozoites, focusing on specific molecular interactions between host and parasite.

Recent findings: Recent work highlights the central role of host-parasite interactions at virtually every stage of RBC invasion by merozoites. Biophysical experiments have for the first time measured the strength of merozoite-RBC attachment during invasion. For P. falciparum, there have been many key insights regarding the invasion ligand PfRh5 in particular, including its influence on host species tropism, a co-crystal structure with its RBC receptor basigin, and its suitability as a vaccine target. For P. vivax, researchers identified the origin and emergence of the parasite from Africa, demonstrating a natural link to the Duffy-negative RBC variant in African populations. For the simian parasite P. knowlesi, zoonotic invasion into human cells is linked to RBC age, which has implications for parasitemia during an infection and thus malaria.

Summary: New studies of the molecular and cellular mechanisms governing RBC invasion by Plasmodium parasites have shed light on various aspects of parasite biology and host cell tropism, and indicate opportunities for malaria control.

Figure 1. An overview of RBC invasion by Plasmodium merozoites

Following release into the bloodstream with rupture of an infected RBC, a merozoite encounters a new RBC and requires only ~1-2 minutes to complete re-invasion to establish a new round of the cell cycle. During encounter, the merozoite and the RBC undergo an ordered series of adhesive interactions, most of which are mediated by interaction of RBC receptors with parasite proteins, or invasion ligands, anchored to the merozoite plasma membrane surface. 1) A free merozoite can attach at any point of its cell body to the RBC. During this primary phase of encounter, adhesion is very dynamic, but interaction culminates in 2) direct, oriented attachment of merozoite apical end to the RBC membrane that is more stable. RBC receptors engage parasite invasion ligands on the parasite apical surface. These invasion ligands are secreted onto the merozoite apical end from micronemes and anterior necks of the rhoptry organelles. To the right, we schematically depict known P. falciparum invasion ligands. Where the RBC receptor for a given ligand is known, this molecule is also identified. PfRh5 forms a functional complex with P. falciparum Rh5-interacting protein (PfRIPR) and the glycophosphatidylinositol-conjugated protein CyRPA. For AMA1, the receptor RON2 is secreted by the parasite into the RBC membrane. 3) Oriented RBC attachment is clearly separated from a subsequent phase, where the parasite uses its own actin-based cytoskeletal machinery to burrow and enter the RBC cytoplasmic space. After apical attachment but before intracellular entry, the merozoite creates a “junction” with the RBC that seals the plasma membranes of the two cells. This tight junction (also called moving junction) acts as a foothold for the parasite as it enters the RBC, forming a circumferential ring around the parasite that also demarcates the nascent parasitophorous vacuole (PV) from the RBC membrane. Formation of the PV itself is stimulated by discharge of the rhoptry, which results in secretion of protein and lipid into the RBC following apical attachment. 4) Invasion is completed when the PV, which will house the parasite through its ensuing development and replication, pinches off the from the RBC membrane into the host cytoplasm, with the vestige of the tight junction still apparent at the posterior. While most invaded parasites re-enter the asexual cell cycle for further parasite proliferation, a small fraction commit to gametocytogenesis, a developmental program for terminal sexual-stage differentiation that ensures parasite transmission. Circulating gametocytes, when taken up by a feeding mosquito, undergo sexual recombination and further differentiation for re-infection of another individual.