title: Placental Sequestration of Plasmodium falciparum Malaria Parasites Is Mediated by the Interaction Between VAR2CSA and Chondroitin Sulfate A on Syndecan-1.
abstract: During placental malaria, Plasmodium falciparum infected erythrocytes sequester in the placenta, causing health problems for both the mother and fetus. The specific adherence is mediated by the VAR2CSA protein, which binds to placental chondroitin sulfate (CS) on chondroitin sulfate proteoglycans (CSPGs) in the placental syncytium. However, the identity of the CSPG core protein and the cellular impact of the interaction have remain elusive. In this study we identified the specific CSPG core protein to which the CS is attached, and characterized its exact placental location. VAR2CSA pull-down experiments using placental extracts from whole placenta or syncytiotrophoblast microvillous cell membranes showed three distinct CSPGs available for VAR2CSA adherence. Further examination of these three CSPGs by immunofluorescence and proximity ligation assays showed that syndecan-1 is the main receptor for VAR2CSA mediated placental adherence. We further show that the commonly used placental choriocarcinoma cell line, BeWo, express a different set of proteoglycans than those present on placental syncytiotrophoblast and may not be the most biologically relevant model to study placental malaria. Syncytial fusion of the BeWo cells, triggered by forskolin treatment, caused an increased expression of placental CS-modified syndecan-1. In line with this, we show that rVAR2 binding to placental CS impairs syndecan-1-related Src signaling in forskolin treated BeWo cells, but not in untreated cells.
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Copenhagen University Hospital, Denmark.
authors.forename: Marina
authors.initials: M
authors.lastname: Ayres Pereira
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Copenhagen University Hospital, Denmark.|Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandel Clausen
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Copenhagen University Hospital, Denmark.
authors.forename: Caroline
authors.identifier: 0000-0002-5736-4847
authors.initials: C
authors.lastname: Pehrson
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.|Copenhagen Center for Glycomics and Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark.
authors.forename: Yang
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Copenhagen University Hospital, Denmark.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Resende
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Mads
authors.initials: M
authors.lastname: Daugaard
authors.affiliation: Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Anders
authors.initials: A
authors.lastname: Riis Kristensen
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Copenhagen University Hospital, Denmark.
authors.forename: Charlotte
authors.identifier: 0000-0002-6811-3891
authors.initials: C
authors.lastname: Spliid
authors.affiliation: Section of Environmental Health, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Line
authors.identifier: 0000-0002-3210-159X
authors.initials: L
authors.lastname: Mathiesen
authors.affiliation: Section of Environmental Health, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lisbeth
authors.identifier: 0000-0002-9576-1202
authors.initials: L
authors.lastname: E Knudsen
authors.affiliation: Department of Obstetrics, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Damm
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Copenhagen University Hospital, Denmark.
authors.forename: Thor
authors.initials: T
authors.lastname: G Theander
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical Sciences, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: R Hansson
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Copenhagen University Hospital, Denmark.
authors.forename: Morten
authors.identifier: 0000-0003-2668-4992
authors.initials: M
authors.lastname: A Nielsen
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Copenhagen University Hospital, Denmark.
authors.forename: Ali
authors.initials: A
authors.lastname: Salanti
mesh_terms: D000953:Antigens, Protozoan / Q000378:metabolism*; D002809:Chondroitin Sulfates / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D016778:Malaria, Falciparum / Q000378:metabolism / Q000469:parasitology*; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D010920:Placenta / Q000378:metabolism / Q000469:parasitology*; D010963:Plasmodium falciparum; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000378:metabolism / Q000469:parasitology*; D053668:Syndecan-1 / Q000378:metabolism*
chemical_list: D000953:Antigens, Protozoan; C508241:SDC1 protein, human; D053668:Syndecan-1; C512601:VAR2CSA protein, Plasmodium falciparum; D002809:Chondroitin Sulfates