The structural motif in chondroitin sulfate for adhesion of Plasmodium falciparum-infected erythrocytes comprises disaccharide units of 4-O-sulfated and non-sulfated N-acetylgalactosamine linked to glucuronic acid.
An important characteristic of malaria parasite Plasmodium falciparum-infected red blood cells (IRBCs) is their ability to adhere to host endothelial cells and accumulate in various organs. Sequestration of IRBCs in the placenta, associated with excess perinatal and maternal mortality, is mediated in part by adhesion of parasites to the glycosaminoglycan chondroitin sulfate A (CSA) present on syncytiotrophoblasts lining the placental blood spaces. To define key structural features for parasite interactions, we isolated from CSA oligosaccharide fractions and established by electrospray mass spectrometry and high performance liquid chromatography disaccharide composition analysis their differing chain length, sulfate content, and sulfation pattern. Testing these defined oligosaccharide fragments for their ability to inhibit IRBC adhesion to immobilized CSA revealed the importance of non-sulfated disaccharide units in combination with 4-O-sulfated disaccharides for interaction with IRBCs. Selective removal of 6-O-sulfates from oligo- and polysaccharides to increase the proportion of non-sulfated disaccharides enhanced activity, indicating that 6-O-sulfation interferes with the interaction of CSA with IRBCs. Dodecasaccharides with four or five 4-O-sulfated and two or one non-sulfated disaccharide units, respectively, comprise the minimum chain length for effective interaction with IRBCs. Comparison of the activities of CSA and CSB oligo- and polysaccharides with a similar sulfation pattern and content achieved from partial desulfation demonstrated that glucuronic acid rather than iduronic acid residues are important for IRBC binding.
Chai
Wengang
W
Medical Research Council Glycosciences Laboratory, Imperial College School of Medicine, Northwick Park Hospital, Harrow, Middlesex HA1 3UJ, United Kingdom. w.chai@ic.ac.uk
Beeson
James G
JG
Lawson
Alexander M
AM
D000116:Acetylgalactosamine / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D002448:Cell Adhesion; D002809:Chondroitin Sulfates / Q000737:chemistry* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004187:Disaccharides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism / Q000382:microbiology*; D020723:Glucuronic Acid / Q000378:metabolism; D006603:Hexuronic Acids / Q000737:chemistry; D009005:Monosaccharides / Q000737:chemistry; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism; D010963:Plasmodium falciparum / Q000378:metabolism*; D011134:Polysaccharides / Q000737:chemistry; D011485:Protein Binding; D021241:Spectrometry, Mass, Electrospray Ionization; D013455:Sulfur / Q000378:metabolism; D014574:Uronic Acids / Q000737:chemistry
D004187:Disaccharides; D006603:Hexuronic Acids; D009005:Monosaccharides; D009844:Oligosaccharides; D011134:Polysaccharides; D014574:Uronic Acids; D013455:Sulfur; D020723:Glucuronic Acid; D002809:Chondroitin Sulfates; D000116:Acetylgalactosamine