Molecular Basis of Sequestration in Severe and Uncomplicated Plasmodium falciparum Malaria: Differential Adhesion of Infected Erythrocytes to CD36 and ICAM-l

Ockenhouse, CF; Ho, May; Tandon, NN; Seventer, Gijs A. van; Shaw, Steve; White, Nicholas J.; Ga, Jamieson; Chulay, J. D.; Webster, H. K.

doi:10.1093/infdis/164.1.163

Cited by 199 publications

(145 citation statements)

References 26 publications

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“…Parasites were synchronized as described previously at the early ring stage with 5% sorbitol for 5 min (51). Selection of C4S Adherent IRBCs-The C4S-adherent parasites (3D7 clone) were originally selected from the NF-54 laboratory strains by the panning procedure (52). Tissue culture plastic Petri dishes were coated overnight with a sterile 10 g/ml solution of bovine trachea C4S in PBS, pH 7.2, at room temperature in a tissue culture hood, and then blocked with a 2% sterile solution of BSA in PBS for 1 h. Synchronized cultures of the parasites with 10 -20% parasitemia at the late trophozoite or mid-schizont stage were harvested, washed two times with RPMI 1640 medium without serum, suspended at 2% hematocrit, layered on C4S-coated Petri dishes, and incubated at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Structural Requirements for the Adherence ofPlasmodium falciparum-infected Erythrocytes to Chondroitin Sulfate Proteoglycans of Human Placenta

Alkhalil¹,

Achur²,

Valiyaveettil³

et al. 2000

Journal of Biological Chemistry

107

157

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Plasmodium falciparum infection during pregnancy results in the accumulation of infected red blood cells (IRBCs) in the placenta, leading to poor pregnancy outcome. In the preceding paper (Achur, R.N., Valiyaveettil, M., Alkhalil, A., Ockenhouse, C. F., and Gowda, D.C. (2000) J. Biol. Chem. 275, 40344 -40356), we reported that unusually low sulfated chondroitin sulfate proteoglycans (CSPGs) in the intervillous spaces of the placenta mediate the IRBC adherence. In this study, we report the structural requirements for the adherence and the minimum chondroitin 4-sulfate (C4S) structural motif that supports IRBC adherence. Partially sulfated C4Ss with varying sulfate contents were prepared by solvolytic desulfation of a fully sulfated C4S. These and other nonmodified C4Ss, with different proportions of 4-, 6-, and nonsulfated disaccharide repeats, were analyzed for inhibition of IRBC adherence to the placental CSPG. C4Ss containing 30 -50% 4-sulfated and 50 -70% nonsulfated disaccharide repeats efficiently inhibited IRBC adherence; C6S had no inhibitory activity. Oligosaccharides of varying sizes were prepared by the partial depolymerization of C4Ss containing varying levels of 4-sulfation, and their ability to inhibit the IRBC adherence was studied. Oligosaccharides with six or more disaccharide repeats inhibited IRBC adherence to the same level as that of the intact C4Ss, indicating that a dodecasaccharide is the minimum structural motif required for optimal IRBC adherence. Of the C4S dodecasaccharides, only those with two or three sulfate groups per molecule showed maximum IRBC inhibition. These data define the structural requirements for the IRBC adherence to placental CSPGs with implications for the development of therapeutics for maternal malaria.

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Section: Methodsmentioning

confidence: 99%

Structural Requirements for the Adherence ofPlasmodium falciparum-infected Erythrocytes to Chondroitin Sulfate Proteoglycans of Human Placenta

Alkhalil¹,

Achur²,

Valiyaveettil³

et al. 2000

Journal of Biological Chemistry

107

157

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“…The central pathophysiologic events in severe Plasmodium falciparum malaria are the inability of the host defenses to control parasite replication, cytokine imbalance resulting in the excessive release of proinflammatory cytokines in response to infection, and the sequestration of parasitized erythrocytes (PEs) 3 in the microvasculature of vital organs (2)(3)(4)(5)(6). Several receptors have been implicated in the cytoadherence of PEs to vascular endothelium, including ICAM-1 (7)(8), VCAM-1 (9 -10), E-selectin (10), platelet/endothelial cell adhesion molecule-1/CD31 (11), chondroitin-4-sulfate (12), hyaluronic acid (13), thrombospondin (TSP) (14), ␣ v ␤ 3 (15), and CD36 (16 -20).…”

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confidence: 99%

“…CD36, an 88-kDa integral protein found on endothelial cells, adipocytes, platelets, monocytes, and macrophages (m s), has been shown to be a receptor preferentially recognized by most natural isolates of P. falciparum (7,9,21). 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).…”

mentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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

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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“…These strains bound to several adhesion molecules including ICAM-1, but with low affinity (Table 3, reference 35). Certain malaria strains selected for ICAM-1 binding displayed a reduced ability to interact with other adhesion molecules, such as CD36 (35). This may suggest that high and low affinity binding sites exist on ICAM-1.…”

mentioning

confidence: 99%

In vivo sequestration of Plasmodium falciparum-infected human erythrocytes: a severe combined immunodeficiency mouse model for cerebral malaria.

Willimann

Matile

Weiss

et al. 1995

The Journal of Experimental Medicine

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SummaryCerebral malaria is a fatal complication of infection by Plasmodiumfakiparum in man. The neurological symptoms that characterize this form of malarial disease are accompanied by the adhesion of infected erythrocytes to the vasculature of the brain. To study this phenomenon in vivo, an acute phase severe combined immunodeficiency (SCID) mouse model was developed in which sequestration of P.fakiparum-infected human erythrocytes took place. During acute cerebral malaria in humans, the expression of intercellular adhesion molecule-1 (ICAM-1) is induced in vascular endothelium by inflammatory reactions. Acute phase ICAM-1 expression can also be obtained in SCID mice. The endothelium of the midbrain region was the most responsive to such inflammatory stimulus. It is noteworthy that the reticular formation in the midbrain controls the level of consciousness, and loss of consciousness is a symptom of cerebral malaria. We found that infected human erythrocytes were retained 24 times more than normal erythrocytes in ICAM-1-positive mouse brain. Sequestration to the brain was reduced by anti-ICAM-1 antibodies. These in vivo results were confirmed by the binding of P. fakiparum-infected erythrocytes to the ICAM-l-positive endothelium in tissue sections of mouse brain. We conclude that the SCID mouse serves as a versatile in vivo model that allows the study ofP.fakiparum-infected erythrocyte adhesion as it occurs in human cerebral malaria. Upregulation of ICAM-1 expression in the region of the midbrain correlates with increased retention of malaria-infected erythrocytes and with the symptoms of cerebral malaria.p , lasmodium falciparum, one of the four plasmodium spedes that infect man, produces a fulminant disease that can lead to severe cerebral symptoms. Every year, this parasite causes about 250 million clinical cases of malaria (1). Approximately 2 million individuals, mainly children under 5 years of age, die from the main complications, which are cerebral malaria and severe anemia. A special feature of P. falciparum pathology is the absence of mature intraerythrocytic stages of the parasite in the circulating blood. Mature forms are found attached to the lining of microvessels in peripheral organs. This adhesion of infected erythrocytes to the vascular endothelium is called sequestration. Clinically severe neurological symptoms correlate with a much higher frequency of sequestered parasitized erythrocytes in the brain vasculature compared to other organs (2).Sequestration is thought to depend on differences between P.fakiparum strains leading to the expression of different erythrocyte surface molecules mediating adhesion to endothelia, as well as variation in the production of endotoxins eliciting a TNF-ot response by host macrophages (3). Thus, sequestration depends also on the susceptibility of the host to endotoxins, the subsequent regulation of adhesion molecules, and the host's level of immunity (4). A key role is played by TNF. Its plasma concentration levels are elevated in patients with fatal cerebral m...

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Molecular Basis of Sequestration in Severe and Uncomplicated Plasmodium falciparum Malaria: Differential Adhesion of Infected Erythrocytes to CD36 and ICAM-l

Cited by 199 publications

References 26 publications

Structural Requirements for the Adherence ofPlasmodium falciparum-infected Erythrocytes to Chondroitin Sulfate Proteoglycans of Human Placenta

Structural Requirements for the Adherence ofPlasmodium falciparum-infected Erythrocytes to Chondroitin Sulfate Proteoglycans of Human Placenta

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

In vivo sequestration of Plasmodium falciparum-infected human erythrocytes: a severe combined immunodeficiency mouse model for cerebral malaria.

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