The Semiconserved Head Structure of Plasmodium falciparum Erythrocyte Membrane Protein 1 Mediates Binding to Multiple Independent Host Receptors

Abstract

Erythrocytes infected with mature forms of Plasmodium falciparum do not circulate but are withdrawn from the peripheral circulation; they are bound to the endothelial lining and to uninfected erythrocytes in the microvasculature.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.

Binding of Plasmodium falciparum-infected erythrocytes to soluble platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31): frequent recognition by clinical isolates.

“…13 We have shown that pRBCs adhere to the N-terminal part of PECAM-1/CD31 and that this binding is mediated by the cysteine-rich inter-domain region (CIDR) and Duffy binding like domain-2␦ (DBL-2␦) of P. falciparum erythrocyte membrane protein 1 (PfEMP1). 14 However, it is likely that additional parasite-derived ligands expressed on the surface of pRBCs may also contribute to this binding since treatment of pRBCs with trypsin in concentrations that will cleave off PfEMP-1 does not completely abrogate PECAM-1/CD31 binding. 15,16 Since the common assays for investigating cytoadherence are dependent on parasitemia to a large extent, we have developed an assay in which soluble fluorescent PECAM-1/ CD31 (sfPECAM-1/CD31) is bound to the surface of pRBCs in suspension.…”

Nonimmune immunoglobulin binding and multiple adhesion characterize Plasmodium falciparum -infected erythrocytes of placental origin

“…It is known that pRBCs of isolates from children with severe malaria have the capacity to interact with multiple receptors, and PfEMP1 variants having multiple adhesive domains have been reported (8,18). Therefore, we reasoned that it is possible that placental isolates have similarly adopted alternative adhesion͞ evasion strategies.…”

“…The adverse effects of PAM decrease with succeeding pregnancies and have been linked to the development of protective antibodies that recognize an antigenically and functionally distinct subpopulation of pRBCs (5)(6)(7). Whereas parasites from nonpregnant individuals interact with CD36 and several other receptors (8,9), the glycosaminoglycan (GAG) chondroitin sulfate A (CSA) has been described as the main placental receptor (5, 10). Recent observations imply that structurally distinct var genes, var2CSA, encode the CSA-binding PfEMP1 variant implicated in PAM, raising hope for the development of a vaccine (11)(12)(13)(14).…”

The Low Sulfated Chondroitin Sulfate Proteoglycans of Human Placenta Have Sulfate Group-clustered Domains That Can Efficiently Bind Plasmodium falciparum-infected Erythrocytes

“…P. falciparum EMP1 can bind, in a domain-specific manner, CD36, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, platelet endothelial cell adhesion molecule-1/CD31, and thrombospondin on vascular endothelial cell surface (18 -24). In addition, P. falciparum EMP1 can also bind complement receptor (25), heparan sulfate (20), and chondroitin 4-sulfate (C4S) (22)(23)(24)(25)(26)(27)(28). Thus, the parasite, by its ability to express divergent P. falciparum EMP1s using the var gene repertoire, can adhere to various organs.…”