title: Heparan sulfate on endothelial cells mediates the binding of Plasmodium falciparum-infected erythrocytes via the DBL1alpha domain of PfEMP1.
abstract: Plasmodium falciparum may cause severe forms of malaria when excessive sequestration of infected and uninfected erythrocytes occurs in vital organs. The capacity of wild-type isolates of P falciparum-infected erythrocytes (parasitized red blood cells [pRBCs]) to bind glycosaminoglycans (GAGs) such as heparin has been identified as a marker for severe disease. Here we report that pRBCs of the parasite FCR3S1.2 and wild-type clinical isolates from Uganda adhere to heparan sulfate (HS) on endothelial cells. Binding to human umbilical vein endothelial cells (HUVECs) and to human lung endothelial cells (HLECs) was found to be inhibited by HS/heparin or enzymes that remove HS from cell surfaces. (35)S-labeled HS extracted from HUVECs bound directly to the pRBCs' membrane. Using recombinant proteins corresponding to the different domains of P falciparum erythrocyte membrane protein 1 (PfEMP1), we identified Duffy-binding-like domain-1alpha (DBL1alpha) as the ligand for HS. DBL1alpha bound in an HS-dependent way to endothelial cells and blocked the adherence of pRBCs in a dose-dependent manner. (35)S-labeled HS bound to DBL1alpha-columns and eluted as a distinct peak at 0.4 mM NaCl. (35)S-labeled chondroitin sulfate (CS) of HUVECs did not bind to PfEMP1 or to the pRBCs' membrane. Adhesion of pRBCs of FCR3S1.2 to platelet endothelial cell adhesion molecule-1 (PECAM-1)/CD31, mediated by the cysteine-rich interdomain region 1alpha (CIDR1alpha), was found be operative with, but independent of, the binding to HS. HS and the previously identified HS-like GAG on uninfected erythrocytes may act as coreceptors in endothelial and erythrocyte binding of rosetting parasites, causing excessive sequestration of both pRBCs and RBCs.
authors.affiliation: Microbiology and Tumor Biology Center (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Vogt
authors.forename: Antonio
authors.initials: A
authors.lastname: Barragan
authors.forename: Qijun
authors.initials: Q
authors.lastname: Chen
authors.forename: Fred
authors.initials: F
authors.lastname: Kironde
authors.forename: Dorothe
authors.initials: D
authors.lastname: Spillmann
authors.forename: Mats
authors.initials: M
authors.lastname: Wahlgren
mesh_terms: D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000737:chemistry*; D004910:Erythrocyte Membrane / Q000378:metabolism / Q000469:parasitology; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006497:Heparan Sulfate / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D010963:Plasmodium falciparum / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism*; D013462:Sulfur Radioisotopes; D014454:Uganda; D014471:Umbilical Veins
chemical_list: D006497:Heparan Sulfate; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D015800:Protozoan Proteins; D013462:Sulfur Radioisotopes; C085731:erythrocyte membrane protein 1, Plasmodium falciparum