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

Alkhalil, Abdulnaser; Achur, Rajeshwara N.; Valiyaveettil, Manojkumar; Ockenhouse, Christian F.; Gowda, D. Channe

doi:10.1074/jbc.m006399200

Cited by 107 publications

(172 citation statements)

References 66 publications

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“…C4S with 36% 4-sulfate was prepared by the regioselective 6-O-desulfation of bovine trachea C4S/C6S copolymer as described previously (51) and fractionation of the product by DEAE-Sephacel chromatography. 2 C4S 6-mers with 36% 4-sulfate was prepared by the digestion of C4S containing 36% 4-sulfate group with testicular hyaluronidase and fractionation of the oligosaccharides by gel filtration on Bio-Gel P-6.…”

Section: Methodsmentioning

confidence: 99%

“…The parasites were cultured using type O-positive human red blood cells at 3% hematocrit in RPMI 1640 medium supplemented with 25 mM HEPES, 29 mM sodium bicarbonate, 0.005% hypoxanthine, p-aminobenzoic acid (2 mg/ liter), gentamycin sulfate (50 mg/liter), and 10% O-positive human serum. The cultures were incubated at 37°C in an atmosphere of 90% nitrogen, 5% oxygen, and 5% carbon dioxide (51).…”

Section: Methodsmentioning

confidence: 99%

“…2 C4S 6-mers with 36% 4-sulfate was prepared by the digestion of C4S containing 36% 4-sulfate group with testicular hyaluronidase and fractionation of the oligosaccharides by gel filtration on Bio-Gel P-6. 2 C4Ss with 3 and 11% 4-sulfate groups were prepared by the solvolytic desulfation of a fully 4-sulfated C4S from sturgeon notochord as described previously (51).…”

Section: Methodsmentioning

confidence: 99%

“…These CSPGs were found to be unusually low sulfated; on an average, only ϳ8% of the disaccharide repeating units of the CS chains of placental CSPGs are 4-sulfated, and the remainder are nonsulfated (50). In previous studies, we have also shown that IRBC adhesion involves the participation of both nonsulfated and 4-sulfated disaccharide repeating units and the optimal binding requires ϳ30% 4-sulfated and ϳ70% nonsulfated disaccharide repeats (51). Further, we established that a C4S motif having six disaccharide repeating units (6-mer) with two 4-sulfated and four nonsulfated disaccharide units is the minimum structural motif required for optimal binding of IRBCs (51).…”

mentioning

confidence: 98%

“…In previous studies, we have also shown that IRBC adhesion involves the participation of both nonsulfated and 4-sulfated disaccharide repeating units and the optimal binding requires ϳ30% 4-sulfated and ϳ70% nonsulfated disaccharide repeats (51). Further, we established that a C4S motif having six disaccharide repeating units (6-mer) with two 4-sulfated and four nonsulfated disaccharide units is the minimum structural motif required for optimal binding of IRBCs (51). A recent study confirmed most of our findings (52), except that four or five rather than two of the disaccharide repeating units of the binding motif containing six-disaccharide repeating units needs to be 4-sulfated for effective IRBC binding.…”

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confidence: 99%

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

Achur

Valiyaveettil

Gowda

2003

Journal of Biological Chemistry

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Plasmodium falciparum infection in pregnant women results in the chondroitin 4-sulfate-mediated adherence of the parasite-infected red blood cells (IRBCs) in the placenta, adversely affecting the health of the fetus and mother. We have previously shown that unusually low sulfated chondroitin sulfate proteoglycans (CSPGs) in the intervillous spaces of the placenta are the receptors for IRBC adhesion, which involves a chondroitin 4-sulfate motif consisting of six disaccharide moieties with ϳ30% 4-sulfated residues. However, it was puzzling how the placental CSPGs, which have only ϳ8% of the disaccharide 4-sulfated, could efficiently bind IRBCs. Thus, we undertook to determine the precise structural features of the CS chains of placental CSPGs that interact with IRBCs. We show that the placental CSPGs are a mixture of two major populations, which are similar by all criteria except differing in their sulfate contents; 2-3% and 9 -14% of the disaccharide units of the CS chains are 4-sulfated, and the remainder are nonsulfated. The majority of the sulfate groups in the CSPGs are clustered in CS chain domains consisting of 6 -14 repeating disaccharide units. While the sulfate-rich regions of the CS chains contain 20 -28% 4-sulfated disaccharides, the other regions have little or no sulfate. Further, we find that the placental CSPGs are able to efficiently bind IRBCs due to the presence of 4-sulfated disaccharide clusters. The oligosaccharides corresponding to the sulfate-rich domains of the CS chains efficiently inhibited IRBC adhesion. Thus, our data demonstrate, for the first time, the unique distribution of sulfate groups in the CS chains of placental CSPGs and that these sulfate-clustered domains have the necessary structural elements for the efficient adhesion of IRBCs, although the CS chains have an overall low degree of sulfation.A distinctive feature of Plasmodium falciparum compared with the other three human malaria parasites is its ability to express adherent protein(s) on the surfaces of the infected red blood cells (IRBCs) 1 and thereby sequester in the microvascular capillaries of various organs by adhering to endothelial cell surfaces (1-5). The extensive accumulation of IRBCs in vital organs causes capillary blockage with deprivation of oxygen and nutrients and production of toxic levels of proinflammatory cytokines (3, 6 -10), damaging the endothelial lining and causing organ dysfunction and severe pathological conditions. A number of studies have shown that the adherent protein expressed on the surfaces of IRBCs to be P. falciparum erythrocyte membrane protein 1 (EMP1), a multidomain, antigenic var gene family protein (11-17). 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-sulfa...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

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

Achur

Valiyaveettil

Gowda

2003

Journal of Biological Chemistry

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Genesis of placental sequestration in malaria and possible targets for drugs for placental malaria

Clark

2019

Birth Defects Research

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Malaria during pregnancy results in intrauterine growth restriction, fetal anemia, and infant mortality. Women are more susceptible to malaria during pregnancy due to malaria-induced inflammation and the sequestration of infected red blood cells in the placenta, which bind to the chondroitin sulfate portion of syndecan-1 on the syncytiotrophoblast and in the intervillous space. Syndecan-1 is a dimeric proteoglycan with an extracellular ectodomain that is cleaved from the transmembrane domain (referred to as "shedding") by matrix metalloproteinases (MMPs), likely the secreted MMP-9. The ectodomain includes four binding sites for chondroitin sulfate, which are proximal to the transmembrane domain, and six distal binding sites primarily for heparan sulfate. This "shedding" of syndecan-1 is inhibited by the presence of the heparan sulfate chains, which can be removed by heparanase. The intervillous space contains fibrin strands and syndecan-1 ectodomains free of heparan sulfate. The following is proposed as the sequence of events that leads to and is primarily responsible for sequestration in the intervillous space of the placenta. Inflammation associated with malaria triggers increased heparanase activity that degrades the heparan sulfate on the membrane-bound syndecan-1. Inflammation also upregulates MMP-9 and the removal of heparan sulfate gives MMP-9 access to cleave syndecan-1, thereby releasing dimeric syndecan-1 ectodomains with at least four chondroitin sulfate chains attached. These multivalent ectodomains bind infected RBCs together leading to their aggregation and entrapment in intervillous fibrin. This mechanism suggests possible new targets for anti-placental malaria drugs such as the inhibition of MMP-9. Doxycycline is an antimalarial drug which inhibits MMP-9. K E Y W O R D Sfibrin, heparanase, malaria, metalloproteinase, placenta, sequestration, syndecan-1

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Toward Libraries of Biotinylated Chondroitin Sulfate Analogues: From Synthesis to In Vivo Studies

Despras

Bernard

Perrot

et al. 2012

Chemistry A European J

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Chondroitin sulfate-E (CS-E) oligosaccharidic analogues (di to hexa) were prepared from lactose. In these compounds, the 2-acetamido group was replaced by a hydroxyl group. This modification speeded up the synthesis, and large oligosaccharides were constructed in a few steps from a lactose-originated block. The protecting groups used were as follows; Fmoc for hydroxyl groups to be glycosylated, allyl group for anomeric position protection, and trichoroacetimidate leaving groups were used to prepare up to octasaccharides. We took advantage of the presence of allyl group to develop a click biotinylation, through its transformation into a 3-azido-2-hydroxyl propyl group in two steps (epoxidation and sodium azide epoxide opening). The biotinylating agent was a water-soluble propargylated and biotinylated triethylene glycol (PEG). By using surface plasmon resonance (SPR), it was shown that the di-, tetra-, and hexasaccharides display a binding affinity and selectivity toward HSF/GSF and CXCL12 similar to that of CS-E. A parallel study confirmed their mimicry of natural compounds, based on the hexasaccharide interaction with Otx2, a homeodomain protein involved in brain maturation, thus validating our simplification approach to synthesize bioactive GAG.

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

Cited by 107 publications

References 66 publications

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

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

Genesis of placental sequestration in malaria and possible targets for drugs for placental malaria

Toward Libraries of Biotinylated Chondroitin Sulfate Analogues: From Synthesis to In Vivo Studies

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