Surface Molecules on Plasmodium falciparum-Infected Erythrocytes Involved in Adherence

Rj, Howard; Handunnetti, SM; Hasler, Thomas; Gilladoga, AD; Aguiar, J. C. de; Pasloske, Brittan L.; Morehead, K.; Albrecht, Geneviève; Schravendijk, M R van

doi:10.4269/ajtmh.1990.43.15

Cited by 27 publications

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“…Although the plasmodial molecules on the surface of the malaria-infected erythrocyte that are responsible for binding to the endothelium have not been identified, a parasite-encoded protein, P. falciparum erythrocyte membrane protein 1 (PfEMP 1; ref. 4), similar to a recently described protein called sequestrin (5), has been correlated with cytoadherence. However, the precise role of PfEMP 1 (or sequestrin) in erythrocyte sequestration has not been determined.…”

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“…Putative receptors on the endothelial cell for the P. falciparum-infected erythrocyte have been reported to be CD36, intercellular adhesion molecule 1, and thrombospondin (4,25,26). The identity of the receptor for the band 3-related adhesin is not known; however, if, as has been suggested, multiple adhesive mechanisms are involved in sequestration, then the receptor affected by synthetic peptides based on band 3 motifs must constitute a major component of adhesion/sequestration, since peptide infusion is sufficient to result in large-scale appearance of mature forms in the peripheral circulation.…”

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Synthetic peptides based on motifs present in human band 3 protein inhibit cytoadherence/sequestration of the malaria parasite Plasmodium falciparum.

Crandall

Collins

Gysin

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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Synthetic peptides patterned on the amino acid sequences found in two exofacial regions of band 3 protein (residues 824-829 of loop 7 and residues 547-553 of loop 3) blocked, in a dose-dependent fashion, the in vitro adherence of Plasmodium falciparum-infected erythrocytes to C32 amelanotic melanoma cells. Intravenous infusion of these synthetic peptides into Aotus and Saimiri monkeys infected with sequestering isolates of P. fakciparum resulted in the appearance of mature forms of the parasite in the peripheral circulation. The finding that the peptides were effective as adhesion blockers in the micromolar range suggests that cerebral malaria could be managed through antiadhesion therapy.The hallmark ofPlasmodiumfalciparum infections is sequestration-that is, the attachment of erythrocytes infected with mature-stage parasites (trophozoites/schizonts) to the endothelial cells lining the postcapillary venules (1). In humans, the principal organs in which sequestration takes place are the heart, lung, kidney, and liver (2). Sequestration in the brain microvessels-a special pathology of P. falciparum infections called cerebral malaria-may occlude blood flow and result in confusion, lethargy, and deep coma (3). Although the plasmodial molecules on the surface of the malaria-infected erythrocyte that are responsible for binding to the endothelium have not been identified, a parasite-encoded protein, P. falciparum erythrocyte membrane protein 1 (PfEMP 1; ref. 4), similar to a recently described protein called sequestrin (5), has been correlated with cytoadherence. However, the precise role of PfEMP 1 (or sequestrin) in erythrocyte sequestration has not been determined.Earlier work (5-7) indicated that infection of erythrocytes by the malaria parasite P. falciparum leads to truncated forms ofband 3 protein in the erythrocyte membrane and that these were involved in the cytoadherent behavior of the infected erythrocyte. Further, several monoclonal antibodies directed against exofacial loops 3 and 7 of band 3 protein blocked cytoadherence (I.C. and I.W.S., unpublished results). In an attempt to further define the regions of band 3 protein responsible for the cytoadherent behavior of infected erythrocytes, peptides patterned on the surface-exposed domains of band 3 were synthesized, and their ability to inhibit the in vitro and in vivo adherence of P. falciparuminfected erythrocyte was determined.The following observations were used to determine which sequences in the exofacial loops (Fig. 1) might contain the adhesive region: (i) Cytoadherence is strongly influenced by pH (16,17), consistent with a protonated histidine residue being near to, or part of, the adhesin site. (ii) Cytoadherence is strongly inhibited by the iodination of surface proteins of a P. falciparum-infected erythrocyte (18), implying that a tyrosine residue is near to, or part of, the adhesin site. (iii) The adhesin is trypsin sensitive (18), suggesting that a trypsin site (a lysine or arginine) is close to, or part of, the adhesive region. Bec...

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confidence: 99%

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confidence: 99%

Synthetic peptides based on motifs present in human band 3 protein inhibit cytoadherence/sequestration of the malaria parasite Plasmodium falciparum.

Crandall

Collins

Gysin

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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“…All wild isolates of P fifciparum that cytoadhere in vitro are knob-positive to date (13). Since the PRBC receptor(s) for both CD36 and TSP are localized around the knobs, these structures are therefore important for the localization of cytoadherence proteins.…”

Section: Discussionmentioning

confidence: 99%

“…filccipancnt that does not sequester in vessels or in vitro, (b) all wild isolates of E! filccipamm that exhibit cytoadherence in vivo are knob-positive (13), and (c) based on the morphological observations by electron microscopy, PRBC attachment to endothelial cells seems to occur at knob protrusions of the PRBC surface membrane in ex vivo and in vitro samples (15), as well as in clinical samples from cerebral malaria patients (5,6,16).…”

Section: Introductionmentioning

confidence: 98%

Plasmodium falciparum-infected erythrocyte receptor(s) for CD36 and thrombospondin are restricted to knobs on the erythrocyte surface.

Nakamura

Hasler²,

Morehead³

et al. 1992

J Histochem Cytochem.

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Adherence of Plasmodium falciparum-infected RBCs (PRBC) to endothelial cells causes PRBC sequestration in cerebral microvessels and is considered to be a major contributor to the pathogenesis of cerebral malaria. Both CD36 and thrombospondin (TSP) are glycoproteins that mediate PRBC adherence to endothelial cells in vitro. Because they are both expressed on the surface of endothelial cells, they probably contribute to PRBC sequestration and vascular occlusion in vivo. By applying affinity labeling of receptor binding sites with purified ligands, we showed for the first time that both CD36 and TSP can bind independently to the PRBC surface and that the PRBC receptor(s) for CD36 and TSP are localized specifically to the electron-dense knob protrusions of the PRBC surface. These findings may help in efforts to develop a malaria vaccine to prevent cerebral malaria.

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“…Several molecules mediating infected erythrocyte adherence to vascular endothelial cells have been identified but remain less well characterized than parasite molecules from other parts of the life cycle (45). One is sequestrin, a 270-kDa protein expressed on the surface of infected erythrocytes and the ligand for CD36, a recognition protein expressed by vascular endothelium and its experimental surrogate, C32 melanoma cells.…”

Section: Transmission-blocking and Pathogenicity Antigensmentioning

confidence: 99%

Malaria vaccine development

Jones

Hoffman

1994

Clin Microbiol Rev

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The malaria parasite life cycle presents several targets for attack, but these different parts of the life cycle are susceptible to different types of host immune response. For example, the sporozoite is most sensitive to immune antibody, while liver stage parasites can be eliminated by cytotoxic T lymphocytes. Attachment of merozoites to erythrocytes, on the other hand, can be blocked by antibody. Convincing experimental evidence shows that completely protective immunity to malaria can be induced. The challenge now is to design recombinant or synthetic vaccines that induce the right types of immune responses to specific life cycle stages. This requires the identification and characterization of B- and T-lymphocyte epitopes expressed by the parasite or by parasitized host cells. These epitopes must be incorporated into a delivery system that maximizes the interaction between the vaccine epitopes and the host immune system. Many epitopes from several parts of the life cycle are already characterized; development of multivalent vaccines, that is, vaccines which contain immunogens from more than one part of the life cycle, is a promising area for research efforts.

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Surface Molecules on Plasmodium falciparum-Infected Erythrocytes Involved in Adherence

Cited by 27 publications

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Synthetic peptides based on motifs present in human band 3 protein inhibit cytoadherence/sequestration of the malaria parasite Plasmodium falciparum.

Synthetic peptides based on motifs present in human band 3 protein inhibit cytoadherence/sequestration of the malaria parasite Plasmodium falciparum.

Plasmodium falciparum-infected erythrocyte receptor(s) for CD36 and thrombospondin are restricted to knobs on the erythrocyte surface.

Malaria vaccine development

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