title: Structural interactions in chondroitin 4-sulfate mediated adherence of Plasmodium falciparum infected erythrocytes in human placenta during pregnancy-associated malaria.
abstract: Infection with Plasmodium falciparum during pregnancy results in the adherence of infected red blood cells (IRBCs) in placenta, causing pregnancy-associated malaria with severe health complications in mothers and fetuses. The chondroitin 4-sulfate (C4S) chains of very low sulfated chondroitin sulfate proteoglycans (CSPGs) in placenta mediate the IRBC adherence. While it is known that partially sulfated but not fully sulfated C4S effectively binds IRBCs, structural interactions involved remain unclear and are incompletely understood. In this study, structurally defined C4S oligosaccharides of varying sulfate contents and sizes were evaluated for their ability to inhibit the binding of IRBCs from different P. falciparum strains to CSPG purified from placenta. The results clearly show that, with all parasite strains studied, dodecasaccharide is the minimal chain length required for the efficient adherence of IRBCs to CSPG and two 4-sulfated disaccharides within this minimal structural motif are sufficient for maximal binding. Together, these data demonstrate for the first time that the C4S structural requirement for IRBC adherence is parasite strain-independent. We also show that the carboxyl group on nonreducing end glucuronic acid in dodecasaccharide motif is important for IRBC binding. Thus, in oligosaccharides containing terminal 4,5-unsaturated glucuronic acid, the nonreducing end disaccharide moiety does not interact with IRBCs due to the altered spatial orientation of carboxyl group. In such C4S oligosaccharides, 14-mer but not 12-mer constitutes the minimal motif for inhibition of IRBC binding to placental CSPG. These data have important implications for the development and evaluation of therapeutics and vaccine for placental malaria.
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Rajeshwara N
authors.initials: RN
authors.lastname: Achur
authors.forename: Ikuko
authors.initials: I
authors.lastname: Kakizaki
authors.forename: Suchi
authors.initials: S
authors.lastname: Goel
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kojima
authors.forename: SubbaRao V
authors.initials: SV
authors.lastname: Madhunapantula
authors.forename: Atul
authors.initials: A
authors.lastname: Goyal
authors.forename: Misato
authors.initials: M
authors.lastname: Ohta
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
authors.forename: Keiichi
authors.initials: K
authors.lastname: Takagaki
authors.forename: D Channe
authors.initials: DC
authors.lastname: Gowda
mesh_terms: D000116:Acetylgalactosamine / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D011508:Chondroitin Sulfate Proteoglycans / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000494:pharmacology*; D004903:Erythrocyte Aggregation / Q000187:drug effects*; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000469:parasitology*; D005260:Female; D020723:Glucuronic Acid / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood*; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology; D010920:Placenta / Q000098:blood supply* / Q000473:pathology; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000097:blood* / Q000378:metabolism
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D009844:Oligosaccharides; D020723:Glucuronic Acid; D002809:Chondroitin Sulfates; D000116:Acetylgalactosamine