release of sequestered malaria parasites upon injection of a glycosaminoglycan释放的疟疾寄生虫注入一种粘多糖.pdfVIP

Release of Sequestered Malaria Parasites upon Injection of a Glycosaminoglycan 1 1 1 2 1 1 Anna M. Vogt , Fredrik Pettersson , Kirsten Moll , Cathrine Jonsson , Johan Normark , Ulf Ribacke , 3 4 5 1 1* Thomas G. Egwang , Hans-Peter Ekre , Dorothe Spillmann , Qijun Chen , Mats Wahlgren 1 Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden and Swedish Institute for Infectious Disease Control, Solna, Sweden, 2 Department of Nuclear Medicine, Karolinska University Hospital, Solna, Sweden, 3 Med Biotech Laboratories, Kampala, Uganda, 4 Dilafor AB, Stockholm, Sweden, 5 Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden 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-vascu