Invasion by P. falciparum Merozoites Suggests a Hierarchy of Molecular Interactions

Open Access
Publisher Website
Google Scholar
Abstract
Central to the pathology of malaria disease are the repeated cycles of parasite invasion and destruction of human erythrocytes. In Plasmodium falciparum, the most virulent species causing malaria, erythrocyte invasion involves several specific receptor–ligand interactions that direct the pathway used to invade the host cell, with parasites varying in their dependency on these different pathways. Gene disruption of a key invasion ligand in the 3D7 parasite strain, the P. falciparum reticulocyte binding-like homolog 2b (PfRh2b), resulted in the parasite invading via a novel pathway. Here, we show results that suggest the molecular basis for this novel pathway is not due to a molecular switch but is instead mediated by the redeployment of machinery already present in the parent parasite but masked by the dominant role of PfRh2b. This would suggest that interactions directing invasion are organized hierarchically, where silencing of dominant invasion ligands reveal underlying alternative pathways. This provides wild parasites with the ability to adapt to immune-mediated selection or polymorphism in erythrocyte receptors and has implications for the use of invasion-related molecules in candidate vaccines. The repeated cycles of parasite invasion and destruction of human red cells is central to malaria disease. In Plasmodium falciparum, the most virulent species that causes malaria, invasion involves the interaction of several parasite ligands with receptors that line the red cell surface. Central to the success of the P. falciparum parasite is its ability not only to utilize a number of these receptors but also to vary the primary route used. Here we show that in some parasite strains when you remove their key invasion ligands, rather than activating an alternative molecular machinery to compensate, the parasite has at its disposal a secondary means of invading that was present in the parent parasite but whose role was masked by the dominant invasion route. This suggests that the interactions that direct invasion are organized hierarchically, where silencing of the dominant ligand reveals underlying alternative means to invade. Such a mechanism gives the parasite population the ability to avoid host immune-mediated selection or to adapt to variation in red cell surface receptors and still successfully infect the human host. This stresses the importance of directing a blood-stage malaria vaccine at multiple receptor–ligand interactions to prevent parasite adaptation to invade via alternative routes.