Release of sequestered malaria parasites upon injection of a glycosaminoglycan

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.
Synopsis Severe Plasmodium falciparum malaria is common and in part the result of an excessive binding of infected erythrocytes in the microvasculature. The parasite employs heparan sulfate during the adherence to the vascular endothelium and to erythrocytes. Heparin, which is related to heparan sulfate in that it is composed of the same building blocks, was here periodate-treated to generate depolymerized glycosaminoglycans (dGAGs) that possess no anticoagulant activity. The dGAGs disrupt erythrocyte and endothelial binding of P. falciparum–infected erythrocytes in vitro. An intravenous injection of dGAGs blocks infected erythrocytes from binding in the micro-vasculature of the rat and releases already sequestrated parasites into circulation both in the rat and in a non-human primate. If this approach is successfully translated to the clinical setting, it may offer help to patients whereby the injection of a dGAG releases already sequestered parasite-infected erythrocytes and re-establishes the micro-vascular blood flow. The authors suggest dGAGs to be promising candidates of adjunct therapy that may have an important impact on malaria mortality.