title: Interactions with heparin-like molecules during erythrocyte invasion by Plasmodium falciparum merozoites.
abstract: During erythrocyte invasion, Plasmodium falciparum merozoites use multiple receptor-ligand interactions in a series of coordinated events, but current knowledge of these interactions is limited. Using real-time imaging of invasion, we established that heparin-like molecules block early, and essential, events in erythrocyte invasion by merozoites. All P falciparum isolates tested, and parasites using different invasion pathways were inhibited to comparable levels. Furthermore, it was not possible to select for heparin-resistant parasites. Heparin-like molecules occur naturally on the surface of human erythrocytes, where they may act as receptors for binding of merozoite surface proteins. Consistent with this, we demonstrated that MSP1-42, a processed form of merozoite surface protein 1 (MSP1) involved in invasion, bound heparin in a specific manner; furthermore, binding was observed with the secondary processing fragment MSP1-33, but not MSP1-19. We defined key structural requirements of heparin-like molecules for invasion inhibition and interactions with MSP1-42. Optimal activity required a degree of sulfation more than or equal to 2, disulfation of the N-acetylglucosamine or hexuronic acid residue, and a minimum chain length of 6 monosaccharides. These findings have significant implications for understanding P falciparum invasion of erythrocytes and the development of novel therapeutics and vaccines.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Boyle
authors.forename: Jack S
authors.initials: JS
authors.lastname: Richards
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gilson
authors.forename: Wengang
authors.initials: W
authors.lastname: Chai
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
mesh_terms: D000818:Animals; D001665:Binding Sites; D004912:Erythrocytes / Q000378:metabolism* / Q000469:parasitology*; D006493:Heparin / Q000097:blood* / Q000737:chemistry; D006790:Host-Parasite Interactions / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D020066:Merozoite Surface Protein 1 / Q000737:chemistry / Q000502:physiology; D052940:Merozoites / Q000502:physiology; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology; D010963:Plasmodium falciparum / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011956:Receptors, Cell Surface / Q000502:physiology
chemical_list: D020066:Merozoite Surface Protein 1; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D006493:Heparin