Erythrocytes infected with mature forms of Plasmodium falciparum do not circulate but are withdrawn from the peripheral circulation; they are bound to the endothelial lining and to uninfected erythrocytes in the microvasculature. Blockage of the blood flow, hampered oxygen delivery, and severe malaria may follow if binding is excessive. The NH2-terminal head structure (Duffy binding–like domain 1 [DBL1α]–cysteine-rich interdomain region [CIDR1α]) of a single species of P. falciparum erythrocyte membrane protein 1 (PfEMP1) is here shown to mediate adherence to multiple host receptors including platelet-endothelial cell adhesion molecule 1 (PECAM-1)/CD31, the blood group A antigen, normal nonimmune immunoglobulin M, three virulence-associated receptor proteins, a heparan sulfate–like glucosaminoglycan, and CD36. DBL2δ was found to mediate additional binding to PECAM-1/CD31. The exceptional binding activity of the PfEMP1 head structure and its relatively conserved nature argues that it holds an important role in erythrocyte sequestration and therefore in the virulence of the malaria parasite.

The sequestration of Plasmodium falciparum-infected erythrocytes (pRBC) away from the peripheral circulation is a property of all field isolates. Here we have examined the pRBC of 111 fresh clinical isolates from children with malaria for a number of adhesive features in order to study their possible coexpression and association with severity of disease. A large number of adhesion assays were performed studying rosetting, giant rosetting, and binding to CD36, intercellular adhesion molecule 1, platelet endothelial cell adhesion molecule 1, thrombospondin, heparin, blood group A, and immunoglobulins. Suspension assays were performed at the actual parasitemia of the isolate, while all the static adhesion assays were carried out at an equal adjusted parasitemia. The ability to bind to multiple receptors, as well as the ability to form rosettes and giant rosettes, was found to be more frequent among isolates from children with severe versus mild malaria (P ‫؍‬ 0.0015). Rosettes and giant rosettes were more frequent for children with severe malaria, and the cell aggregates were larger and tighter, than for those with mild disease (P ‫؍‬ 0.0023). Binding of immunoglobulins (97% of isolates) and of heparin (81% of isolates) to infected erythrocytes was common, and binding to heparin and blood group A was associated with severity of disease (P ‫؍‬ 0.011 and P ‫؍‬ 0.031, respectively). These results support the idea that isolates that bind to multiple receptors are involved in the causation of severe malaria and that several receptor-ligand interactions work synergistically in bringing about severe disease.

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Excessive binding of Plasmodium falciparum-infected red blood cells (pRBCs) to the vascular endothelium (cytoadherence) and to uninfected erythrocytes (rosetting) may lead to occlusion of the microvasculature and thereby contribute directly to the acute pathology of severe human malaria. A number of endothelial receptors have been identified as targets for the pRBCs, including CD36, intercellular adhesion molecule-1 (ICAM-1) and chondroitin-4-sulfate (CSA). In vitro, CD36 is the most frequent target of strains from patients with mild as well as severe P. falciparum malaria, but is expressed at low levels on the cerebral microvasculature and therefore seems unlikely to be involved in the evolution of cerebral disease. Strains of P. falciparum that form rosettes are associated both with the occurrence of cerebral malaria and severe anemia. Here we report that malaria-infected RBCs adhere to platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) on the vascular endothelium. pRBCs bind to endothelial cells, to PECAM-1/CD31 transfected cells, and directly to recombinant PECAM-1/CD31 absorbed onto plastic. Soluble PECAM-1/CD31 and monoclonal antibodies specific for the amino-terminal segment of PECAM-1/CD31 (domains 1-4) blocked the binding. Interferon-gamma (IFN-gamma)-essential for the development of cerebral malaria in the mouse-was found to augment adhesion of human pRBCs to PECAM-1/CD31 on endothelial cell monolayers. Our results suggest that PECAM-1/CD31 is a virulence-associated endothelial receptor of P. falciparum-infected RBCs.

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