Comparative genomics of drug resistance in Trypanosoma brucei rhodesiense.
Comparative genomics of drug resistance in Trypanosoma brucei rhodesiense.
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DOI：
10.1007/s00018-016-2173-6
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发表时间：
2016-09
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影响因子：
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通讯作者：
Mäser P
中科院分区：
文献类型：
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作者：
Graf FE;Ludin P;Arquint C;Schmidt RS;Schaub N;Kunz Renggli C;Munday JC;Krezdorn J;Baker N;Horn D;Balmer O;Caccone A;de Koning HP;Mäser P
布氏罗得西亚锥虫是人类昏睡病的病原体之一，昏睡病是一种由采采蝇传播的致命疾病，仅限于撒哈拉以南非洲。在这里，我们研究两个独立的T。B.在2年的过程中，已经用药物美拉胂醇和喷他脒选择的罗得西亚杆菌，直到它们表现出前所未有的稳定的交叉耐药性。我们应用比较基因组学和转录组学来识别潜在的突变。只有少数突变在选择过程中被固定下来。在两个品系中，三个基因受到突变的影响：氨基嘌呤转运蛋白AT 1、水通道蛋白AQP 2和RNA结合蛋白UBP 1。美拉胂醇选择的品系携带包括腺苷转运蛋白基因AT 1的大缺失，而喷他脒选择的品系携带AT 1的杂合点突变G430 R，这使得转运蛋白无功能。两个抗性品系都丢失了AQP 2，并且两个品系在UBP 1的RNA结合基序中携带相同的点突变R131 L。这一发现表明，已知的T. B.布氏杆菌未能复制T. B.罗得西亚突变体表明UBP 1在美拉胂醇-喷他脒交叉耐药性中可能发挥作用。UBP 1-Leu 131在T. B.布氏杆菌不影响对美拉胂醇或喷他脒的敏感性。本文的在线版本（doi：10.1007/s 00018 -016-2173-6）包含补充材料，可供授权用户使用。
Trypanosoma brucei rhodesiense is one of the causative agents of human sleeping sickness, a fatal disease that is transmitted by tsetse flies and restricted to Sub-Saharan Africa. Here we investigate two independent lines of T. b. rhodesiense that have been selected with the drugs melarsoprol and pentamidine over the course of 2 years, until they exhibited stable cross-resistance to an unprecedented degree. We apply comparative genomics and transcriptomics to identify the underlying mutations. Only few mutations have become fixed during selection. Three genes were affected by mutations in both lines: the aminopurine transporter AT1, the aquaporin AQP2, and the RNA-binding protein UBP1. The melarsoprol-selected line carried a large deletion including the adenosine transporter gene AT1, whereas the pentamidine-selected line carried a heterozygous point mutation in AT1, G430R, which rendered the transporter non-functional. Both resistant lines had lost AQP2, and both lines carried the same point mutation, R131L, in the RNA-binding motif of UBP1. The finding that concomitant deletion of the known resistance genes AT1 and AQP2 in T. b. brucei failed to phenocopy the high levels of resistance of the T. b. rhodesiense mutants indicated a possible role of UBP1 in melarsoprol–pentamidine cross-resistance. However, homozygous in situ expression of UBP1-Leu131 in T. b. brucei did not affect the sensitivity to melarsoprol or pentamidine. The online version of this article (doi:10.1007/s00018-016-2173-6) contains supplementary material, which is available to authorized users.