Placental Sequestration of Plasmodium falciparum Malaria Parasites Is Mediated by the Interaction Between VAR2CSA and Chondroitin Sulfate A on Syndecan-1

PLoS Pathogens

Lisbeth E. Knudsen¹  Anders Riis Kristensen¹  Yang Mao¹  Marina Ayres Pereira¹  Morten A. Nielsen¹  Thomas Mandel Clausen¹  Mads Daugaard²  Mafalda Resende³  Stefan R. Hansson⁴  Ali Salanti⁵  Line Mathiesen⁶  Peter Damm⁷  Thor G. Theander⁷  Caroline Pehrson⁸  Charlotte Spliid⁸ 

[1] Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen and Copenhagen University Hospital, Denmark;Copenhagen Center for Glycomics and Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark;Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America;Department of Obstetrics, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;Division of Obstetrics and Gynecology, Department of Clinical Sciences, Lund University Hospital, Lund University, Lund, Sweden;Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada;Section of Environmental Health, Department of Public Health, University of Copenhagen, Copenhagen, Denmark;Vancouver Prostate Centre, Vancouver, BC, Canada

关键词: Red blood cells;    Parasitic diseases;    Composite images;    Malarial parasites;    Malaria;    Immunostaining;    Membrane staining;    Nuclear staining;   

DOI  :  10.1371/journal.ppat.1005831

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY