Sticking for a Cause: The Falciparum Malaria Parasites Cytoadherence Paradigm

Abstract

After a successful invasion, malaria parasite Plasmodium falciparum extensively remodels the infected erythrocyte cellular architecture, conferring cytoadhesive properties to the infected erythrocytes. Cytoadherence plays a central role in the parasite's immune-escape mechanism, at the same time contributing to the pathogenesis of severe falciparum malaria. In this review, we discuss the cytoadhesive interactions between P. falciparum infected erythrocytes and various host cell types, and how these events are linked to malaria pathogenesis. We also highlight the limitations faced by studies attempting to correlate diversity in parasite ligands and host receptors with the development of severe malaria.

Keywords: Plasmodium; cytoadherence; host immune responses; malaria; pathogenesis.

Figure 1

Schematic diagram depicting life cycles of Plasmodium falciparum, involving Anopheles mosquito and human hosts, where the stages in humans can be furthered divided into liver (exoerythrocytic) and erythrocytic stages.

Figure 2

Schematic diagram to illustrate the postulated chronology and mechanism of P. falciparum sequestration and pathogenesis in deep vasculature. The blue arrows on top of the diagram represent the direction of blood flow from arteriole to venule. (A) Cytoadhesion of IRBCs on endothelial cells causes endothelial inflammation. In addition, rosette formation at the capillary junctions opening into venules also contributes to the hampering of blood flow within the vasculature. The endothelial inflammation by direct IRBC-cytoadherence, coupled with hampering of blood flood stimulate the affected endothelial cells (pink halo) to release various substances in response to the changes in its environment. (B) Some of the components released by the endothelial cells (blue halo) may reverse and prevent IRBC-endothelial cytoadhesion, at the same time stimulate rosette formation. Rosetting mechanically prevents IRBCs from binding to endothelial cells while enabling the IRBCs to sequester in larger microvasculature. This will enable the parasite to escape splenic clearance. This switch of cytoadhesive characteristics also prevents complete occlusion of blood flow, thus minimizing, if not preventing irreversible tissue damages from tissue hypoxia. (C) However, for hosts with endothelial cells that are not as well-responsive to IRBC-endothelial cytoadhesion and slowing down of blood flow, the components that can reverse and prevent IRBC-endothelial cytoadhesion may be inadequate to exert such effect. As a result, vasculature occlusion ensures. At the same time, endothelial injury and vasculature leakage worsen (black halo), which may lead to fatal outcome.