Structure and synthesis of nematode phosphorylcholine-containing glycoconjugates.
Infection with filarial nematodes produces a chronic, long-lasting illness with adult worms able to survive within human hosts for up to 15 years. A contributor to the longevity of these parasites is the presence of phosphorylcholine (PC) on components of the worms' molecular secretions (ES). PC on ES modulates host immune responses towards an anti-inflammatory phenotype thereby generating an environment favourable for parasite survival. PC is attached to nematode ES via a covalent association with carbohydrate, which, although well-documented in bacteria and fungi, is absent from humans, making it an ideal target for the development of novel drugs. In order to produce such drugs it is first necessary to understand the structure and synthesis of nematode PC-glycans. ES-62 is the major PC-ES-product of Acanthocheilonema viteae and is a homologue of PC-ES found in human filarial nematodes. We have studied the structure and biosynthesis of PC-glycans of ES-62 by a combination of pulse-chase experiments, experiments involving the use of inhibitors of each of intracellular trafficking, oligosaccharide processing and phospholipid biosynthesis and various forms of mass spectrometry. Our indications indicate that PC is transferred in the lumen of the medial Golgi to an N-type glycan consisting of a trimannosyl core with or without core fucosylation bearing between 1 and 4 N-acetyl glucosamine residues. The structure of the PC-N-glycans found in ES-62 appears to be conserved amongst filarial nematodes in that it has additionally been identified in Onchocerca volvulus and O. gibsoni. Also, similar structures have been found in non-filarial parasitic nematodes and in the free-living nematode Caenorhabditis elegans. Finally, PC has also been recently found attached to the carbohydrate moieties of nematode glycosphingolipids and the structure of these will also be considered.
Houston
K M
KM
The University of Strathclyde, Department of Immunology, Strathclyde Institute for Biomedical Sciences, Glasgow G4 0NR.
Harnett
W
W
D000818:Animals; D015195:Drug Design; D005369:Filaricides / Q000737:chemistry; D006001:Glycoconjugates / Q000096:biosynthesis / Q000737:chemistry*; D015801:Helminth Proteins / Q000737:chemistry; D006801:Humans; D009348:Nematoda / Q000737:chemistry*; D010767:Phosphorylcholine / Q000737:chemistry* / Q000378:metabolism
C435884:ES-62 protein, Acanthocheilonema viteae; D005369:Filaricides; D006001:Glycoconjugates; D015801:Helminth Proteins; D010767:Phosphorylcholine