title: Release of sequestered malaria parasites upon injection of a glycosaminoglycan.
abstract: Severe human malaria is attributable to an excessive sequestration of Plasmodium falciparum-infected and uninfected erythrocytes in vital organs. Strains of P. falciparum that form rosettes and employ heparan sulfate as a host receptor are associated with development of severe forms of malaria. Heparin, which is similar to heparan sulfate in that it is composed of the same building blocks, was previously used in the treatment of severe malaria, but it was discontinued due to the occurrence of serious side effects such as intracranial bleedings. Here we report to have depolymerized heparin by periodate treatment to generate novel glycans (dGAG) that lack anticoagulant-activity. The dGAGs disrupt rosettes, inhibit merozoite invasion of erythrocytes and endothelial binding of P. falciparum-infected erythrocytes in vitro, and reduce sequestration in in vivo models of severe malaria. An intravenous injection of dGAGs blocks up to 80% of infected erythrocytes from binding in the micro-vasculature of the rat and releases already sequestered parasites into circulation. P. falciparum-infected human erythrocytes that sequester in the non-human primate Macaca fascicularis were similarly found to be released in to the circulation upon a single injection of 500 mug of dGAG. We suggest dGAGs to be promising candidates for adjunct therapy in severe malaria.
authors.affiliation: Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Vogt
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pettersson
authors.forename: Kirsten
authors.initials: K
authors.lastname: Moll
authors.forename: Cathrine
authors.initials: C
authors.lastname: Jonsson
authors.forename: Johan
authors.initials: J
authors.lastname: Normark
authors.forename: Ulf
authors.initials: U
authors.lastname: Ribacke
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Egwang
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Ekre
authors.forename: Dorothe
authors.initials: D
authors.lastname: Spillmann
authors.forename: Qijun
authors.initials: Q
authors.lastname: Chen
authors.forename: Mats
authors.initials: M
authors.lastname: Wahlgren
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000469:parasitology* / Q000502:physiology; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D006801:Humans; D008252:Macaca fascicularis; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D008297:Male; D052940:Merozoites / Q000187:drug effects / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012397:Rosette Formation
chemical_list: D006495:Heparin, Low-Molecular-Weight