Figure 1

Junctures of pathogenesis in P. falciparum malaria: cytoadherence of parasitized erythrocytes to microvascular endothelium and parasite invasion of erythrocytes. P. falciparum parasites display knobs at the surface of their host erythrocytes as they mature from ring to trophozoite and schizont forms. PfEMP1 cytoadherence proteins are concentrated on knobs, where they bind receptors (e.g., CD36 and ICAM-1), activate endothelial cells, and recruit blood elements including platelets and white blood cells. By adhering in microvessels, the mature parasites avoid being carried by the bloodstream to the spleen where they are destroyed. Sequestration-related events lead to upregulation of tissue factor, resulting in thrombin and complement activation, platelet activation, cytokine production, endothelial dysfunction and inflammation ¹⁴. To support the transport of PfEMP1 and other proteins including the knob-associated histidine-rich protein (KAHRP) to the erythrocyte membrane, P. falciparum parasites tether membranous Maurer's clefts beneath the cytoskeleton ⁹. In knobs, PfEMP1 associates with KAHRP anchored to spectrin-actin-protein 4.1 complexes, to spectrin-actin junctions, and to the band 3-binding domain of ankyrin ^{15, 16}. Cryklaff et al. ¹ report that P. falciparum remodels host actin into a network of filaments associated with Maurer's clefts and the erythrocyte membrane; this network may support protein and vesicle trafficking to the knobs. Hemoglobin variants HbS and HbC interfere with proper knob formation and PfEMP1 display, weaken the binding of parasitized erythrocytes to endothelium and may thereby reduce sequestration-related pathology ^{5, 8}. Aberrant Maurer's clefts and compromised remodeling of the actin network occur in HbSC and HbCC erythrocytes ¹; these abnormalities remain to be demonstrated in HbAS and HbAC erythrocytes. Inset (left) is adapted from ref ¹⁷. Merozoites released from mature schizonts invade erythrocytes by steps of initial contact, reorientation with attachment, junction formation, and entry and membrane resealing. Most members of the PfEBL and PfRH protein families have overlapping and individually dispensable functions that support a diversity of invasion pathways by attachment to different blood group antigens. These events are followed by binding of P. falciparum AMA1 and RON proteins at the attachment interface, triggering junction formation (not shown) ¹⁸. The interaction of the PfRH5-PfRipr complex ¹² with basigin ² appears to be essential for invasion and may have a critical function beyond the roles of binding and attachment that characterize other members of the PfEBL and PfRH families. Inset (right) is adapted from ref ¹⁸.