Beyond immune escape: a variant surface glycoprotein causes suramin resistance in Trypanosoma brucei
Beyond immune escape: a variant surface glycoprotein causes suramin resistance in Trypanosoma brucei
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DOI：
10.1111/mmi.13854
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发表时间：
2018-01-01
影响因子：
3.6
通讯作者：
Maser, Pascal
中科院分区：
文献类型：
--
作者：
Wiedemar, Natalie;Graf, Fabrice E.;Maser, Pascal
苏拉明是药物化学项目中最早开发的药物之一（拜耳，1916），至今仍然是由罗得西亚布氏锥虫引起的非洲昏睡病血淋巴阶段的首选治疗方法。细胞通过内吞作用摄取苏拉明，并逆转 T. b. 的遗传学研究。 brucei 已将内吞途径的下调与苏拉明抵抗联系起来。在此我们表明，T. brucei spp 中苏拉明抗性的正向选择。培养速度快、重复性高且与抗原变异相关。血流形式的锥虫被一层致密的变异表面糖蛋白（VSG）覆盖，这可以保护它们免受哺乳动物宿主的免疫防御。每个布氏锥虫基因组包含超过 2000 个不同的 VSG 基因，但一次仅表达一个。表达转换为一种特定的 VSG，称为 VSG(Sur)，与苏拉明抵抗相关。在抗性布氏锥虫中重新引入最初表达的 VSG 基因可恢复苏拉明的敏感性。这是关于非洲锥虫抗原变异与耐药性之间联系的第一份报告。
Suramin is one of the first drugs developed in a medicinal chemistry program (Bayer, 1916), and it is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense. Cellular uptake of suramin occurs by endocytosis, and reverse genetic studies with T. b. brucei have linked downregulation of the endocytic pathway to suramin resistance. Herewe show that forward selection for suramin resistance in T. brucei spp. cultures is fast, highly reproducible and linked to antigenic variation. Bloodstream-form trypanosomes are covered by a dense coat of variant surface glycoprotein (VSG), which protects them from their mammalian hosts' immune defenses. Each T. brucei genome contains over 2000 different VSG genes, but only one is expressed at a time. An expression switch to one particular VSG, termed VSG(Sur), correlated with suramin resistance. Reintroduction of the originally expressed VSG gene in resistant T. brucei restored suramin susceptibility. This is the first report of a link between antigenic variation and drug resistance in African trypanosomes.