Carbohydrate-binding agents act as potent trypanocidals that elicit modifications in VSG glycosylation and reduced virulence in Trypanosoma brucei
Carbohydrate-binding agents act as potent trypanocidals that elicit modifications in VSG glycosylation and reduced virulence in Trypanosoma brucei
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DOI：
10.1111/mmi.12359
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发表时间：
2013-11-01
影响因子：
3.6
通讯作者：
Gonzalez-Pacanowska, Dolores
中科院分区：
文献类型：
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作者：
Castillo-Acosta, Victor M.;Vidal, Antonio E.;Gonzalez-Pacanowska, Dolores
布氏锥虫的表面覆盖着一层致密的糖基磷脂酰肌醇锚定的糖蛋白。主要组分是变体表面糖蛋白（VSG），其被少甘露糖和寡甘露糖N-聚糖糖基化。表面聚糖不易接近，肽凝集素-VSG复合物介导的杀伤作用受到主动内吞作用的阻碍。然而，与之前的观察相反，在这里我们表明高亲和力碳水化合物结合剂与表面糖蛋白结合并抑制布氏锥虫血流形式的生长。具体而言，甘露糖特异性朱顶红杂交凝集素（HHA）的结合导致内吞作用和寄生虫裂解的深刻扰动。长时间暴露于HHA导致表面糖蛋白中的三触角寡聚甘露糖结构的损失，作为废除寡糖基转移酶TbSTT 3B基因表达的遗传重排的结果，并产生新的嵌合酶。突变寄生虫表现出显着降低感染性，从而证明了特定的糖基化模式的重要性，寄生虫的毒力。
The surface of Trypanosoma brucei is covered by a dense coat of glycosylphosphatidylinositol-anchored glycoproteins. The major component is the variant surface glycoprotein (VSG) which is glycosylated by both paucimannose and oligomannose N-glycans. Surface glycans are poorly accessible and killing mediated by peptide lectin-VSG complexes is hindered by active endocytosis. However, contrary to previous observations, here we show that high-affinity carbohydrate binding agents bind to surface glycoproteins and abrogate growth of T.brucei bloodstream forms. Specifically, binding of the mannose-specific Hippeastrum hybrid agglutinin (HHA) resulted in profound perturbations in endocytosis and parasite lysis. Prolonged exposure to HHA led to the loss of triantennary oligomannose structures in surface glycoproteins as a result of genetic rearrangements that abolished expression of the oligosaccharyltransferase TbSTT3B gene and yielded novel chimeric enzymes. Mutant parasites exhibited markedly reduced infectivity thus demonstrating the importance of specific glycosylation patterns in parasite virulence.