Heparan Sulfate Proteoglycans Provide a Signal to Plasmodium Sporozoites to Stop Migrating and Productively Invade Host Cells

Coppi, Alida; Tewari, Rita; Bishop, Joseph R.; Bennett, Brandy L.; Lawrence, Roger; Esko, Jeffrey D.; Billker, Oliver; Sinnis, Photini

doi:10.1016/j.chom.2007.10.002

Cited by 231 publications

(275 citation statements)

References 29 publications

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“…The highly sulfated HSPGs of hepatocytes are proposed to mediate targeting of sporozoites to the liver and trigger sporozoite cell invasion (14,15). Heparin and HSPG binding sites have been identified in the CS ectodomain (11,16) and in conserved N-terminal region I and αTSR region II + peptides (12,13,17,18).…”

Section: Resultsmentioning

confidence: 99%

Unexpected fold in the circumsporozoite protein target of malaria vaccines

Doud

Koksal

et al. 2012

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

102

157

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Circumsporozoite (CS) protein is the major surface component of Plasmodium falciparum sporozoites and is essential for host cell invasion. A vaccine containing tandem repeats, region III, and thrombospondin type-I repeat (TSR) of CS is efficacious in phase III trials but gives only a 35% reduction in severe malaria in the first year postimmunization. We solved crystal structures showing that region III and TSR fold into a single unit, an "αTSR" domain. The αTSR domain possesses a hydrophobic pocket and core, missing in TSR domains. CS binds heparin, but αTSR does not. Interestingly, polymorphic T-cell epitopes map to specialized αTSR regions. The N and C termini are unexpectedly close, providing clues for sporozoite sheath organization. Elucidation of a unique structure of a domain within CS enables rational design of next-generation subunit vaccines and functional and medicinal chemical investigation of the conserved hydrophobic pocket.

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Section: Resultsmentioning

confidence: 99%

Unexpected fold in the circumsporozoite protein target of malaria vaccines

Doud

Koksal

et al. 2012

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

102

157

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“…Heterologous expression of ActA in the nonpathogenic species L. innocua allows bacterial internalization in epithelial polarized and nonpolarized cells (Caco-2, MCDK, HeLa, and Vero) but not in COS-1 fibroblasts, suggesting that ActA is sufficient to directly activate an invasion pathway specific for epithelial cells (Suárez et al 2001). The amino-terminal region of ActA is similar to the domain of the Plasmodium falciparum circumsporozoite protein involved in heparate sulfate recognition and hepatocyte binding (Pancake et al 1992;Coppi et al 2007) and it has been shown that the presence of heparan sulfate at the surface of CHO cells is required for the entry of L. monocytogenes in an ActA-dependent manner (Alvarez- Dominguez et al 1997). The in vivo conditions in which the ActA invasion-associated function would be critical for virulence remain to be characterized.…”

Section: Listeria Monocytogenes Entry In Mammalian Epithelial Cellsmentioning

confidence: 95%

Entry of Listeria monocytogenes in Mammalian Epithelial Cells: An Updated View

Pizarro‐Cerdá

Kühbacher

Cossart

2012

Cold Spring Harbor Perspectives in Medicine

226

203

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Listeria monocytogenes is a bacterial pathogen that promotes its internalization into host epithelial cells. Interaction between the bacterial surface molecules InlA and InlB and their cellular receptors E-cadherin and Met, respectively, triggers the recruitment of endocytic effectors, the subversion of the phosphoinositide metabolism, and the remodeling of the actin cytoskeleton that lead to bacterial engulfment. Additional bacterial surface and secreted virulence factors also contribute to entry, albeit to a lesser extent. Here we review the increasing number of signaling effectors that are reported as being subverted by L. monocytogenes during invasion of cultured cell lines. We also update the current knowledge of the early steps of in vivo cellular infection, which, as shown recently, challenges previous concepts generated from in vitro data.

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“…A recent study reported that highly sulfated HSPGs on hepatocytes are involved in the cleavage of a malaria sporozoite protein, known as circumsporozoite protein. Circumsporozoite protein signals the transition from migration to invasion (50). Thrombospondin-related anonymous protein on the surface of sporozoites may interact with HSPGs on hepatocytes (51,52).…”

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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Heparan Sulfate Proteoglycans Provide a Signal to Plasmodium Sporozoites to Stop Migrating and Productively Invade Host Cells

Cited by 231 publications

References 29 publications

Unexpected fold in the circumsporozoite protein target of malaria vaccines

Unexpected fold in the circumsporozoite protein target of malaria vaccines

Entry of Listeria monocytogenes in Mammalian Epithelial Cells: An Updated View

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

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