Plasmodium falciparum erythrocyte invasion: combining function with immune evasion

Abstract

All the symptoms and pathology of malaria are caused by the intraerythrocytic stages of the Plasmodium parasite life cycle. Because Plasmodium parasites cannot replicate outside a host cell, their ability to recognize and invade erythrocytes is an essential step for both parasite survival and malaria pathogenesis. This makes invasion a conceptually attractive vaccine target, especially because it is one of the few stages when the parasite is directly exposed to the host humoral immune system. This apparent vulnerability, however, has been countered by the parasite, which has evolved sophisticated molecular mechanisms to evade the host immune response so that parasites asymptomatically replicate within immune individuals. These mechanisms include the expansion of parasite invasion ligands, resulting in multiple and apparently redundant invasion "pathways", highly polymorphic parasite surface proteins that are immunologically distinct, and parasite proteins which are poorly immunogenic. These formidable defences have so far thwarted attempts to develop an effective blood-stage vaccine, leading many to question whether there really is an exploitable chink in the parasite's immune evasion defences. Here, we review recent advances in the molecular understanding of the P. falciparum erythrocyte invasion field, discuss some of the challenges that have so far prevented the development of blood-stage vaccines, and conclude that the parasite invasion ligand RH5 represents an essential pinch point that might be vulnerable to vaccination.

Figure 1. Erythrocyte invasion is a complex multistep process.

The different stages of erythrocyte invasion are drawn in cartoon form. The different protein families discussed in this review are thought to operate at different steps during invasion, with MSPs functioning at the very earliest stages, PfRH and PfEBAs functioning during the formation of a tight contact between the merozoite apex and the erythrocyte surface, and the AMA1–RON interaction being tightly associated with the moving junction itself , . Detailed reviews of the molecular and ultrastructural basis of invasion are available in other reviews –, .

Figure 2. Plasmodium merozoites face an array of immunological challenges.

Merozoites are the only extracellular stage of the Plasmodium life cycle and are therefore exposed to an array of immune attack mechanisms, as illustrated in cartoon form. Merozoite antigens are known to be the target of antibody responses, which operate both by opsonisation leading to phagocytosis and by simple steric hindrance of receptor–ligand interactions critical for invasion. Complement deposition on the merozoite surface may also play a role in parasite clearance. To avoid these attack mechanisms, Plasmodium parasites have evolved a number of distinct evasion responses. Some merozoite antigens such as AMA1 are highly polymorphic, while members of the PfRH and EBA multigene families are largely redundant and have variable expression profiles. Both of these strategies slow the development of protective immunity by forcing the antibody response to efficiently recognize multiple targets in order to mount an effective response. Finally, RH5 appears to be poorly immunogenic in the context of natural infections, perhaps due to limited levels of expression and exposure.

Figure 3. A molecular understanding of invasion leads to the identification of critical target points.

The invasion events controlled by the paralogues within the EBA and RH families are thought to be redundant with the relative importance of individual genes differing between strains. This leads to a model of invasion where there are a number of parallel “alternative invasion pathways,” as indicated by multiple routes in the diagram for two nominal strains (X and Y). The differential dependencies on particular EBA and RH paralogues is indicated by the weighting of the line, with the unbroken line representing a major dependency and the dashed and dotted lines nonpreferred pathways for that strain. By contrast, the nonredundant RH5–basigin and AMA1–RON2 interactions are represented by critical “bridges.” The immunogenic AMA1 protein is highly variable between strains and is therefore represented by different colours: neutralising host antibodies elicited by one AMA1 variant would not protect against a strain containing a different AMA1 variant. In natural infections, RH5 is not immunogenic, suggesting that the parasite has protected this critical stage by an immunomodulatory mechanism.