The mechanics of malaria parasite invasion of the human erythrocyte - towards a reassessment of the host cell contribution

Abstract

Despite decades of research, we still know little about the mechanics of Plasmodium host cell invasion. Fundamentally, while the essential or non-essential nature of different parasite proteins is becoming clearer, their actual function and how each comes together to govern invasion are poorly understood. Furthermore, in recent years an emerging world view is shifting focus away from the parasite actin-myosin motor being the sole force responsible for entry to an appreciation of host cell dynamics and forces and their contribution to the process. In this review, we discuss merozoite invasion of the erythrocyte, focusing on the complex set of pre-invasion events and how these might prime the red cell to facilitate invasion. While traditionally parasite interactions at this stage have been viewed simplistically as mediating adhesion only, recent work makes it apparent that by interacting with a number of host receptors and signalling pathways, combined with secretion of parasite-derived lipid material, that the merozoite may initiate cytoskeletal re-arrangements and biophysical changes in the erythrocyte that greatly reduce energy barriers for entry. Seen in this light Plasmodium invasion may well turn out to be a balance between host and parasite forces, much like that of other pathogen infection mechanisms.

Figure 1

Mechanisms of host cell entry by intracellular pathogens. Most intracellular pathogens exploit host processes to overcome the intrinsic barriers to cell entry: the host cell membrane and cytoskeleton. A. The endocytic pathway, which regulates a range of cellular functions via controlled receptor internalization and recycling, is exploited by numerous viruses (e.g. rabies virus) to facilitate their own uptake. The process involves the recruitment and subversion of various host proteins (green), which mediate membrane curvature and vesicular scission. Host cell actin (red) polymerization is also required during the internalization process. B. Larger pathogens such as many intracellular bacteria (e.g. Salmonella spp.), protozoa and also certain viruses enter host cells through the initiation of host cell actin‐mediated membrane ruffles that fold over and lead to engulfment of cargo into large intracellular vesicles (macropinosomes). C. The model for apicomplexan cell entry involves active invasion using an actin–myosin motor. This involves myosin treadmilling on polymerized actin connected to apicomplexan surface ligands, which causes an inward movement of the pathogen without a response or involvement of the host cell. ER, endoplasmic reticulum.

Figure 2

Overview of erythrocyte invasion by Plasmodium falciparum merozoites. Initial attachment of the merozoite to the erythrocyte can occur in any orientation. The merozoite then re‐orientates itself to position its apical pole in close contact with the host cell membrane. Numerous parasite host protein interactions occur at this point. Of particular interest are the interactions of EBA175 and Rh4 with their respective host receptors GPA and CR1, which appear to trigger erythrocyte responses visible as membrane deformations. Translocation of the RON complex (blue) across the erythrocyte membrane results in establishment of the tight junction, through which the merozoite enters the host cell into a parasitophorous vacuole utilizing force from its actin–myosin motor.

Figure 3

Model for Plasmodium merozoite invasion‐related protein and host receptor‐mediated cytoskeletal changes during invasion of erythrocytes. A. The erythrocyte actin–spectrin cytoskeleton (blue) is connected to the cell membrane via transmembrane protein (ankyrin and junctional) complexes but is cleared around the invading parasite via an unknown mechanism. B. Bird's eye view of the host cell cytoskeleton. Binding to GPA (red), which is contained within ankyrin and junctional protein complexes, is known to trigger increased cross‐linking of the cytoskeleton to GPA complexes. Tight attachment of parasite‐bound receptor complexes to the cytoskeleton via this route could therefore provide a structural anchor for invasion and/or ‘grip’ to pull open the spectrin mesh around the invading parasite (blue). In contrast, ligation of CR1 is known to cause phosphorylation of the cytoskeletal proteins spectrin and adducin (dotted circles), which are associated with dissociation of actin from the spectrin mesh junctions and increased membrane deformability. Thus, targeting this route could lead to cytoskeletal and mechanical changes that might provide the merozoite with an alternative mechanism of host cytoskeleton clearance at the entry site.