The Pathology of Human Cerebral Malaria

Aikawa, Masamichi; Iseki, Motohiro; Barnwell, John W.; Taylor, Diane Wallace; Oo, Maung Maung; Howard, Russell J.

doi:10.4269/ajtmh.1990.43.30

Cited by 161 publications

(98 citation statements)

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“…The identification of CD36 as a major sequestration receptor has led to the assumption that it contributes to the pathophysiology of severe malaria and has prompted the development of antiadherence therapies to disrupt the CD36-PE interaction (7,18,(22)(23). However, its role in cerebral and severe malaria is unclear because little CD36 is expressed on cerebral microvasculature endothelial cells (5,24), and studies have reported that significantly higher binding of PEs to CD36 occurs in cases of nonsevere malaria (25,26). Furthermore, individuals deficient in CD36 were found to be more susceptible to severe and cerebral malaria (27).…”

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confidence: 99%

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

Serghides

Kain

2001

The Journal of Immunology

101

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Severe and fatal malaria is associated with the failure of host defenses to control parasite replication, excessive secretion of proinflammatory cytokines such as TNF-α, and sequestration of parasitized erythrocytes (PEs) in vital organs. The identification of CD36 as a major sequestration receptor has led to the assumption that it contributes to the pathophysiology of severe malaria and has prompted the development of antiadherence therapies to disrupt the CD36-PE interaction. This concept has been challenged by unexpected evidence that individuals deficient in CD36 are more susceptible to severe and cerebral malaria. In this study, we demonstrate that CD36 is the major receptor mediating nonopsonic phagocytosis of PEs by macrophages, a clearance mechanism of potential importance in nonimmune hosts at the greatest risk of severe malaria. CD36-mediated uptake of PEs occurs via a novel pathway that does not involve thrombospondin, the vitronectin receptor, or phosphatidylserine recognition. Furthermore, we show that proliferator-activated receptor γ-retinoid X receptor agonists induce an increase in CD36-mediated phagocytosis and a decrease in parasite-induced TNF-α secretion. Specific up-regulation of monocyte/macrophage CD36 may represent a novel therapeutic strategy to prevent or treat severe malaria.

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confidence: 99%

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

Serghides

Kain

2001

The Journal of Immunology

101

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“…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).…”

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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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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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“…Ytoadherence of Plasmodium falciparum-infected erythrocytes (IEs) 1 to cerebral postcapillary venular endothelium is a striking feature of the pathology of cerebral malaria (1,2). The phenomenon has been studied in vitro using cell lines such as human endothelial cells (3,4) and C32 melanoma cells (5), and a variety of purified glycoprotein receptors.…”

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Chondroitin sulfate A is a cell surface receptor for Plasmodium falciparum-infected erythrocytes.

Rogerson

Chaiyaroj

et al. 1995

The Journal of Experimental Medicine

319

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SltlmlilaryAdherence of Plasmodium fakiparum-infected erythrocytes to cerebral postcapillary venular endothelium is believed to be a critical step in the development of cerebral malaria. Some of the possible receptors mediating adherence have been identified, but the process of adherence in vivo is poorly understood. We investigated the role of carbohydrate ligands in adherence, and we identified chondroitin sulfate (CS) as a specific receptor for P. falciparum-infected erythrocytes.Parasitized cells bound to Chinese hamster ovary (CHO) cells and C32 melanoma cells in a chondroitin sulfate-dependent manner, whereas glycosylation mutants lacking chondroitin sulfate A (CSA) supported little or no binding. Chondroitinase treatment of wild-type CHO cells reduced binding by up to 90%. Soluble CSA inhibited binding to CHO cells by 99.2 _+ 0.2% at 10 mg/ml and by 72.5 _+ 3.8% at 1 mg/ml, whereas a range of other glycosaminoglycans such as heparan sulfate had no effect. Parasite lines selected for increased binding to CHO cells and most patient isolates bound specifically to immobilized CSA. We conclude that P. falciparum can express or expose proteins at the surface of the infected erythrocyte that mediate specific binding to CSA. This mechanism of adherence may contribute to the pathogenesis of P. J~l-ciparum malaria, but has wider implications as an example of an infectious agent with the capacity to bind specifically to cell-associated or immobilized CS.

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The Pathology of Human Cerebral Malaria

Cited by 161 publications

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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

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

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

Chondroitin sulfate A is a cell surface receptor for Plasmodium falciparum-infected erythrocytes.

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