PECAM-1/CDS31, an endothelial receptor for binding Plasmodium falciparum-infected erythrocytes

Abstract

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.

Platelet power: sticky problems for sticky parasites?

“…Furthermore, although not primary receptors involved in binding, the recruitment of other receptors after initial tethering could nonetheless be important for stabilization of the platelet-infected erythrocyte complex or for triggering functions from them, as is known for other immunological synapses. PECAM-1 is particularly interesting in this respect because it is known to be a ligand for the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of variant surface antigens [9], binds glycosaminoglycans [10] and has been shown to inhibit platelet responses [11,12], suggesting that PECAM-1 triggering might be advantageous to the parasite.…”

Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis ofPlasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-α Secretion by Monocytes/Macrophages

“…Several other receptors including ICAM-1 and CD31 support sequestration of PEs, are expressed on brain endothelium, and are up-regulated by proinflammatory cytokines (8,11,28,(31)(32)(33)59). Secretion of inflammatory cytokines during infection has been associated with a parasite-derived GPI toxin, which stimulates the release of TNF-␣, IL-1, and IL-6 from monocytes and M s. GPI from P. falciparum has also been shown to be a potent inducer of inducible NO synthase and NO output, presumably via the activation of transcription factors such as NF-B and c-rel (28,46).…”

Chondroitin Sulfate Proteoglycan but Not Hyaluronic Acid Is the Receptor for the Adherence of Plasmodium falciparum-Infected Erythrocytes in Human Placenta, and Infected Red Blood Cell Adherence Up-Regulates the Receptor Expression

“…[3][4][5][6][7][8][9][10][11][12] The array of different adhesive mechanisms used by the parasite seems to confer a selective advantage for its efficient survival in the host by switching from one adherent type to another as the host develops adhesion inhibitory antibodies and other phenotype-specific immunity. Thus, in malaria endemic areas, almost all individuals by adulthood develop immunity that effectively controls infection and avoid pathogenesis.…”