Erythrocyte membrane alterations in Plasmodium falciparum malaria sequestration.

Plasmodium falciparum malaria, the most lethal form of human malaria, claims at least 2 million lives worldwide each year. Recently, there has been a significant advance in our understanding of the molecular basis of P. falciparum sequestration, a distinctive pathologic feature that often leads to fatal human cerebral malaria. Parasite-derived VAR proteins (Plasmodium falciparum-infected erythrocyte membrane protein 1) have been cloned and identified as antigenically diverse cytoadherent receptors localized to the knob protrusions that act as attachment points in parasite sequestration. Evidence now supports the hypothesis that cryptic regions of band 3 protein are parasite-induced, host-derived erythrocyte receptors mediating parasite sequestration. Knob structures have been localized to spectrin-actin-protein 4.1 junctions in intact spread membrane skeletons. A recombinant domain of knob-associated histidine-rich protein, a major protein found in both membrane-intact and isolated knobs, has been shown to associate with filamentous actin and spectrin. Parasite- and host-derived erythrocyte membrane proteins involved in P. falciparum sequestration are discussed in this review.