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.
Highlights
Trypanosoma brucei spp are protozoan parasites that cause the neglected disease known as African trypanosomiasis or sleeping sickness in human and nagana in animals, which exhibit a fatal impact on health and economy of the affected countries
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
We have recently reported a new series of carbohydrate-binding agents (CBAs) exhibiting trypanocidal activity in the bloodstream forms [19] in contrast with the established idea that T. brucei does not bind efficiently lectins or that they are degraded in the lysosome after glycoprotein-lectin complex internalization [31]
Summary
Trypanosoma brucei spp are protozoan parasites that cause the neglected disease known as African trypanosomiasis or sleeping sickness in human and nagana in animals, which exhibit a fatal impact on health and economy of the affected countries. The parasites are mainly covered by a single type of variant surface glycoprotein (VSG) at a given moment during infection. Trypanosomes build an effective barrier that protects other invariant proteins of their surface from effectors of the host immune system. A major contribution to the formation of this protective barrier are the N-glycans of the VSGs [1], which contain specific triantennary oligomannose or biantennary paucimannose structures [2,3,4]. The Man5GlcNAc2-PP-Dol structures are responsible of all paucimannose and complex N-glycans, while the Man9GlcNAc2-PP-Dol structures are responsible of all oligomannose-rich N-glycans [7]. N-acetylglucosamine (GlcNAc) is the common core of all N-glycans (paucimannose and oligomannose structures) and is present in hybrid and complex glycans
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