PfEMP1-endothelial receptor interactions mediate microvascular bed–specific sequestration of P. falciparum IEs. (A) The panel shows a typical microvessel found in a variety of organs and tissues in patients with malaria. In the latter half of their 48-hour life cycle, P. falciparum parasites sequester in microvessels and thus avoid clearance from the bloodstream by the spleen. The parasite shown on the left is clonally expressing a PfEMP1 variant on the IE surface that binds CD36 on ECs. In addition to CD36, ECs may also express EPCR, PECAM-1, and ICAM-1. IE binding to these receptors is encoded by specific PfEMP1 domain cassettes (DCs): DC8 and DC13 bind EPCR, DC5 binds PECAM-1, and DC4 binds ICAM-1. Parasites expressing a PfEMP1 variant containing more than one DC presumably bind more than one receptor on individual ECs. Activation of the endothelium by developing parasites and downstream events such as secretion of proinflammatory cytokines, deposition of fibrin, and loss of barrier integrity, result in microvascular inflammation, obstruction, and perivascular leakage. (B) IE sequestration in four different organs. Pregnancy-associated malaria is an organ-specific syndrome initiated by the expression of the PfEMP1 variant VAR2CSA (ie, DC2), which mediates IE binding to placental CSA expressed by syncytiotrophoblasts. In this case, the expression of a specific PfEMP1 variant causes the organ-specific syndrome. In a new model of pathogenesis, CM is initiated by the expression of a PfEMP1 variant containing DC8 or DC13 (green circles), which mediates IE binding to EPCR on brain endothelium. (This same PfEMP1 variant may also contain DC4 [purple circles], which may strengthen the binding of the IE to the same brain EC by binding ICAM-1.) In this case, malaria-induced shedding of the brain’s constitutively low levels of EPCR and PfEMP1-mediated inhibition of EPCR function cause the organ-specific syndrome of CM. In other organs (eg, lung) these same DC8- and DC13-expressing IEs may contribute to disease but other receptor–DC-binding pairs are proposed to cause organ-specific clinical syndromes (eg, respiratory distress). Like CM, respiratory distress and dyserythropoiesis-associated anemia are organ-specific malaria syndromes that may occur alone or in combination with CM. For these two syndromes, it is not yet known whether specific PfEMP1–endothelial receptor interactions, organ-specific differences in expression of endothelial anti- and procoagulants, or both, contribute to their pathology.