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- Title
Exposure of Trypanosoma brucei to an N-acetylglucosamine-Binding Lectin Induces VSG Switching and Glycosylation Defects Resulting in Reduced Infectivity.
- Authors
Castillo-Acosta, Víctor M.; Ruiz-Pérez, Luis M.; Van Damme, Els J. M.; Balzarini, Jan; González-Pacanowska, Dolores
- Abstract
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. Author Summary: Trypanosoma brucei, the causative agent of African trypanosomiasis, is covered by glycosylphosphatidylinositol-anchored glycoproteins, which shield parasites from effectors of the host immune system. The most abundant protein is the variant surface glycoprotein (VSG), which plays an essential role in antigenic variation and the ability of the parasite to evade the immune system. VSGs are N-glycosylated in a site-specific manner by different oligosaccharyltransferases giving rise to complex and mannose-rich N-glycans. In this study, we report that the carbohydrate binding agent, stinging nettle agglutinin (UDA, Urtica dioica), exhibits trypanocidal activity, impairs endocytosis, and cytokinesis and induces parasite lysis. We have investigated the mechanisms conferring resistance in order to understand UDA mode of action and found that resistant strains present changes in the expression of oligosaccharyltransferases, and modifications in the nature of the predominant VSG, therefore resulting in important changes in N-glycan composition. The modification in surface glycans gives rise to reduced infectivity in vivo further underscoring the role of glycosylation in parasite virulence. Our findings show that carbohydrate binding agents that bind effectively to surface glycoproteins can provide a novel avenue for design of drugs to combat African trypanosomiasis.
- Subjects
TRYPANOSOMA brucei; AFRICAN trypanosomiasis; MEMBRANE glycoproteins; GLYCOSYLATION; STINGING nettle
- Publication
PLoS Neglected Tropical Diseases, 2015, Vol 9, Issue 3, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0003612