Exposure of Trypanosoma brucei to an N-acetylglucosamine-binding lectin induces VSG switching and glycosylation defects resulting in reduced infectivity.
Trypanosoma brucei variant surface glycoproteins (VSG) are glycosylated by both paucimannose and oligomannose structures which are involved in the formation of a protective barrier against the immune system. Here, we report that the stinging nettle lectin (UDA), with predominant N-acetylglucosamine-binding specificity, interacts with glycosylated VSGs and kills parasites by provoking defects in endocytosis together with impaired cytokinesis. Prolonged exposure to UDA induced parasite resistance based on a diminished capacity to bind the lectin due to an enrichment of biantennary paucimannose and a reduction of triantennary oligomannose structures. Two molecular mechanisms involved in resistance were identified: VSG switching and modifications in N-glycan composition. Glycosylation defects were correlated with the down-regulation of the TbSTT3A and/or TbSTT3B genes (coding for oligosaccharyltransferases A and B, respectively) responsible for glycan specificity. Furthermore, UDA-resistant trypanosomes exhibited severely impaired infectivity indicating that the resistant phenotype entails a substantial fitness cost. The results obtained further support the modification of surface glycan composition resulting from down-regulation of the genes coding for oligosaccharyltransferases as a general resistance mechanism in response to prolonged exposure to carbohydrate-binding agents.
Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
Víctor M
VM
Castillo-Acosta
Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
Luis M
LM
Ruiz-Pérez
Laboratory of Biochemistry and Glycobiology, Department of Molecular Biotechnology, Ghent University, Ghent, Belgium.
Els J M
EJ
Van Damme
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
Jan
J
Balzarini
Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
Dolores
D
González-Pacanowska
D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004705:Endocytosis; D005260:Female; D006031:Glycosylation; D051379:Mice; D008807:Mice, Inbred BALB C; D037121:Plant Lectins / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000472:pathogenicity; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000378:metabolism*; D014774:Virulence
D037121:Plant Lectins; D014643:Variant Surface Glycoproteins, Trypanosoma; C048862:stinging nettle lectin; D000117:Acetylglucosamine