Effect of Different Fractions of Heparin on Plasmodium falciparum Merozoite Invasion of Red Blood Cells in Vitro

Kulane, Asli; Ekre, Hans-Peter; Perlmann, Peter; Rombo, Lars; Wahlgren, Mats; Wåhlin, B

doi:10.4269/ajtmh.1992.46.589

Cited by 45 publications

(34 citation statements)

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“…Moreover, it has been demonstrated that heparin and other GAGs, but not CSA (40,42), efficiently inhibit the invasion of erythrocytes by the merozoites of different strains of P. falciparum (37,40,42,43). Corroborating these findings, we showed that FucCS inhibited continuous cultivation of P. falciparum in vitro (Fig.…”

Section: Discussionsupporting

confidence: 56%

“…As previous studies have reported, GAGs, including heparin, have major effects on parasite invasion (37,40,70,71); therefore, we investigated the action of FucCS on parasite development by GIA. P. falciparum blood-stage parasites were incubated with native or modified FucCS, as well as heparin or CSA, for 48 h. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, a pivotal role for cytoadherence through the endothelial protein C receptor in the development of severe malaria was described (30). Cytoadhesion of Pf-iEs is mediated by members of the P. falciparum membrane protein 1 (PfEMP-1) family, which mediates parasite interactions with various host receptors, including CD36 (31), intercellular adhesion molecule 1 (ICAM-1) (32), and chondroitin sulfate A (CSA) (33,34), a receptor frequently associated with MiP (15,33,35) Glycosaminoglycans (GAGs), including heparin, have been employed as a strategy to prevent malaria complications due to their abilities to inhibit parasite cytoadhesion, to block invasion, and to disrupt rosettes (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). However, the side effects of heparin, mostly serious bleeding (47), and the potential risk of contamination (because some GAGs are obtained from mammals) have hampered GAG-based adjunct therapies.…”

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confidence: 99%

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Fucosylated Chondroitin Sulfate Inhibits Plasmodium falciparum Cytoadhesion and Merozoite Invasion

Bastos

Albrecht

Kozlowski

et al. 2014

Antimicrob Agents Chemother

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e Sequestration of Plasmodium falciparum-infected erythrocytes (Pf-iEs) in the microvasculature of vital organs plays a key role in the pathogenesis of life-threatening malaria complications, such as cerebral malaria and malaria in pregnancy. This phenomenon is marked by the cytoadhesion of Pf-iEs to host receptors on the surfaces of endothelial cells, on noninfected erythrocytes, and in the placental trophoblast; therefore, these sites are potential targets for antiadhesion therapies. In this context, glycosaminoglycans (GAGs), including heparin, have shown the ability to inhibit Pf-iE cytoadherence and growth. Nevertheless, the use of heparin was discontinued due to serious side effects, such as bleeding. Other GAG-based therapies were hampered due to the potential risk of contamination with prions and viruses, as some GAGs are isolated from mammals. In this context, we investigated the effects and mechanism of action of fucosylated chondroitin sulfate (FucCS), a unique and highly sulfated GAG isolated from the sea cucumber, with respect to P. falciparum cytoadhesion and development. FucCS was effective in inhibiting the cytoadherence of Pf-iEs to human lung endothelial cells and placenta cryosections under static and flow conditions. Removal of the sulfated fucose branches of the FucCS structure virtually abolished the inhibitory effects of FucCS. Importantly, FucCS rapidly disrupted rosettes at high levels, and it was also able to block parasite development by interfering with merozoite invasion. Collectively, these findings highlight the potential of FucCS as a candidate for adjunct therapy against severe malaria.

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Section: Discussionsupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Fucosylated Chondroitin Sulfate Inhibits Plasmodium falciparum Cytoadhesion and Merozoite Invasion

Bastos

Albrecht

Kozlowski

et al. 2014

Antimicrob Agents Chemother

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“…Several studies have already reported that heparin and other sulfated glycoconjugates inhibit the growth of malarial parasites (7)(8)(9)11). In addition, some sulfated chemical compounds inhibit parasite entry into erythrocytes (6,10).…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum BAEBL Binds to Heparan Sulfate Proteoglycans on the Human Erythrocyte Surface

Kobayashi

Kato

Sugi

et al. 2010

Journal of Biological Chemistry

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Erythrocyte invasion is critical to the pathogenesis and survival of the malarial parasite, Plasmodium falciparum. This process is partly mediated by proteins that belong to the Duffy binding-like family, which are expressed on the merozoite surface. One of these proteins, BAEBL (also known as EBA-140), is thought to bind to glycophorin C in a sialic acid-dependent manner. In this report, by the binding assay between recombinant BAEBL protein and enzyme-treated erythrocytes, we show that the binding of BAEBL to erythrocytes is mediated primarily by sialic acid and partially through heparan sulfate (HS). Because BAEBL binds to several kinds of HS proteoglycans or purified HS, the BAEBL-HS binding was found to be independent of the HS proteoglycan peptide backbone and the presence of sialic acid moieties. Furthermore, both the sialic acid-and HS-dependent binding were disrupted by the addition of soluble heparin. This inhibition may be the result of binding between BAEBL and heparin. Invasion assays demonstrated that HS-dependent binding was related to the efficiency of merozoite invasion. These results suggest that HS functions as a factor that promotes the binding of BAEBL and merozoite invasion. Moreover, these findings may explain the invasion inhibition mechanisms observed following the addition of heparin and other sulfated glycoconjugates.Malaria caused by Plasmodium falciparum kills approximately 1 million people per year. After entering the human bloodstream, the parasite propagates asexually via repeated cycles of erythrocyte invasion, cell division, and cell rupture. The process by which the parasitic merozoites invade erythrocytes involves the following steps: attachment, apical reorientation, junction formation, and the formation of a protective parasitophorous vacuole (1).The Duffy binding-like (DBL) 2 family is composed of adhesion molecules that are critical for junction formation between the apical end of the merozoite and the erythrocyte surface.Proteins in this family, such as EBA-175 (erythrocyte-binding antigen-175), are homologous to Plasmodium vivax Duffybinding protein. These proteins contain one or more DBL domains, which are composed of conserved cysteine residues and are associated with erythrocyte binding (2). EBA-175 is bound to glycophorin A on the erythrocyte surface in a sialic acid-dependent manner (3). However, erythrocytes that are treated with neuraminidase remain susceptible to the merozoites of some clones (4), indicating the existence of sialic acidindependent invasion pathways. These alternative pathways are thought to be mediated, at least in part, by other members of the DBL family (5).Parasite growth is inhibited by the addition of heparin, some sulfated saccharide anions, and sulfated chemical compounds (6 -11). Although the inhibition mechanisms remain unclear, these reports suggest the possibility that sulfated moieties play a role in merozoite invasion. In addition to invasion, heparan sulfate (HS) is believed to function as a receptor for PfEMP1 (P. falciparum erythr...

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“…The therapeutic effect of heparin was demonstrated in rhesus monkeys experimentally infected with Plasmodium knowlesi (11). The growth-inhibitory effects of heparin were also described in in vitro studies with P. falciparum (7,24,38) and Theileria sergenti (14). However, the precise mechanisms of its inhibitory capacity against these hemoprotozoa are not fully understood.…”

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confidence: 99%

Growth-Inhibitory Effect of Heparin on Babesia Parasites

Bork

Yokoyama

Ikehara

et al. 2004

Antimicrob Agents Chemother

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We examined the inhibitory effects of three heparins on the growth of Babesia parasites. The multiplication of Babesia bovis, B. bigemina, B. equi, and B. caballi in in vitro cultures and that of B. microti in vivo were significantly inhibited in the presence of heparins, as determined by light microscopy. Treatment with various concentrations of heparin showed complete clearance of the intracellular parasites. Interestingly, a higher percentage of abnormally multidividing B. bovis parasites was observed in the presence of low concentrations of heparin. Furthermore, fluorescein isothiocyanate-labeled heparin was preferably found on the surfaces of extracellular merozoites, as detected by confocal laser scanning microscopy. These findings indicate that the heparin covers the surfaces of babesial merozoites and inhibits their subsequent invasion of erythrocytes.Babesia parasites are tick-transmitted intraerythrocytic protozoa of the phylum Apicomplexa. They affect a wide variety of wild and domestic animals and are responsible for enormous economic losses to the livestock industry worldwide (25). Moreover, some are major etiologic agents of human babesiosis (20). During the asexual growth cycle in a natural host, merozoites internalize the host erythrocytes (RBCs) via multiple adhesive interactions of several protozoan molecules with the host cell surface (45). Thus, the parasites destroy the infected RBCs, which results in severe clinical symptoms, such as high fever, anemia, hematuria, and hemoglobinuria, in the infected hosts. Therefore, understanding of the basic molecular mechanism(s) of the asexual growth cycle, particularly the process of merozoite invasion into the host RBC, may accelerate the development of effective therapeutic methods and methods for the prevention of babesiosis.Heparin is a highly sulfated form of heparan sulfate (HS) (36) and is known to be an inhibitor of the blood coagulation system (19, 23) or as a coreceptor in the binding of fibroblast growth factor to its receptor (29). HS and heparin are complex entities composed of anionic, linear mucopolysaccharides with alternating uronic acid and hexosamine residues in which a limited set of monosaccharide units gives rise to a number of complex sequences by variable substitution with O-sulfate, Nsulfate, and N-acetyl groups (28), rendering the heparin polydisperse (26). While HS is produced in most cell types, heparin is a biosynthetically derived component of mast cells and basophils (16) and has a molecular weight (MW) of approximately 3,000 to 37,500, with an average MW of 13,000 (26). Due to the sulfate and carboxylate residues, heparin is highly negatively charged (9) and, moreover, is often used as a model glycosaminoglycan (GAG) to study the HS interaction with proteins (29).Heparin has also been used for the treatment of patients affected by the cerebral form of Plasmodium falciparum infection (27,30,39). The therapeutic effect of heparin was demonstrated in rhesus monkeys experimentally infected with Plasmodium knowlesi (11). The ...

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Effect of Different Fractions of Heparin on Plasmodium falciparum Merozoite Invasion of Red Blood Cells in Vitro

Cited by 45 publications

References 0 publications

Fucosylated Chondroitin Sulfate Inhibits Plasmodium falciparum Cytoadhesion and Merozoite Invasion

Fucosylated Chondroitin Sulfate Inhibits Plasmodium falciparum Cytoadhesion and Merozoite Invasion

Plasmodium falciparum BAEBL Binds to Heparan Sulfate Proteoglycans on the Human Erythrocyte Surface

Growth-Inhibitory Effect of Heparin on Babesia Parasites

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