Release of Sequestered Malaria Parasites upon Injection of a Glycosaminoglycan

PLoS Pathogens

Dorothe Spillmann¹  Kirsten Moll²  Ulf Ribacke²  Johan Normark²  Anna M Vogt²  Mats Wahlgren²  Fredrik Pettersson²  Qijun Chen²  Cathrine Jonsson³  Hans-Peter Ekre⁴  Thomas G Egwang⁵ 

[1] Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden;Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden and Swedish Institute for Infectious Disease Control, Solna, Sweden;Department of Nuclear Medicine, Karolinska University Hospital, Solna, Sweden;Dilafor AB, Stockholm, Sweden;Med Biotech Laboratories, Kampala, Uganda

关键词: Red blood cells;    Heparin;    Malaria;    Plasmodium;    Macaque;    Malarial parasites;    Sulfates;    Merozoites;   

DOI  :  10.1371/journal.ppat.0020100

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 μg of dGAG. We suggest dGAGs to be promising candidates for adjunct therapy in severe malaria.

【 授权许可】

CC BY