A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance.
A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance.
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DOI：
10.1371/journal.ppat.1011081
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发表时间：
2023-01
期刊：
影响因子：
6.7
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中科院分区：
文献类型：
--
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肝片形吸虫感染在世界范围内造成了巨大的牲畜经济损失，并对流行地区的人类健康构成威胁。控制牲畜的主要药物和唯一获准用于人类的药物是三氯苯达唑（TCBZ）。TCBZ耐药性已在各大洲报告，并威胁到世界许多地区的片形吸虫病的有效控制。迄今为止，了解TCBZ耐药的遗传机制仅限于候选基因的研究，基于对它们在药物作用中的作用的假设。采用另一种方法，我们将遗传杂交与全基因组测序相结合，在1.2Gbp的F.肝细胞癌基因组的TCBZ抗性。我们使用F. hepatica种群，并表明它是该领域药物选择的目标。我们对单个寄生虫进行基因分型，并跟踪SNP的分离和重配，以表明TCBZ抗性表现出孟德尔遗传，并由显性等位基因赋予。我们定义了这个位点的基因含量，以确定参与膜转运的基因，（例如ATP结合盒家族B，ABCB 1）、跨膜信号传导和信号转导（例如GTP-Ras-腺苷酸环化酶和EGF样蛋白）、DNA/RNA结合和转录调控（例如SANT/Myb样DNA结合结构域蛋白）和药物储存和螯合（例如脂肪酸结合蛋白，FABP）作为赋予TCBZ抗性的主要候选物。这项研究构成了第一个实验杂交和全基因组方法的任何遗传性状在F。是了解片形吸虫属耐药性演变的关键。为在现场部署有效的驱虫治疗提供信息。常见的肝吸虫，肝片吸虫，在世界范围内引起牲畜疾病，是一种人畜共患病，导致世界某些地区的人类感染。治疗人类和动物的主要方法是药物三氯苯达唑（TCBZ），因为它对未成熟和成年寄生虫都有活性。虽然对TCBZ的耐药性是控制寄生虫的一个重大威胁，但我们并不确切知道药物如何作用于寄生虫，或者基因组或基因的哪些区域被TCBZ治疗后存活的寄生虫遗传。以前的研究集中在分析被认为与药物作用有关的基因上。在这里，我们采取了一种公正的方法，扫描了实验和自然感染的整个寄生虫基因组，以确定对TCBZ暴露有反应的区域。我们确定了一个小区域，相当于我们实验感染中处于TCBZ选择下的基因组的0.25%。当用TCBZ治疗自然感染的绵羊时，也选择了该基因组区域。我们发现，在治疗中存活下来的寄生虫只需要继承这个抗性区域的一个拷贝，使其成为显性遗传性状。我们发现，耐药区域编码30个基因，并通过表征其功能，我们已经能够确定几个基因，可以赋予TCBZ耐药肝吸虫。我们的研究结果大大推进了对肝吸虫如何对TCBZ产生耐药性的理解，并为分子测试铺平了道路，以检测耐药寄生虫并更有效地在牲畜和人类中进行靶向治疗。
Fasciola hepatica infection is responsible for substantial economic losses in livestock worldwide and poses a threat to human health in endemic areas. The mainstay of control in livestock and the only drug licenced for use in humans is triclabendazole (TCBZ). TCBZ resistance has been reported on every continent and threatens effective control of fasciolosis in many parts of the world. To date, understanding the genetic mechanisms underlying TCBZ resistance has been limited to studies of candidate genes, based on assumptions of their role in drug action. Taking an alternative approach, we combined a genetic cross with whole-genome sequencing to localise a ~3.2Mbp locus within the 1.2Gbp F. hepatica genome that confers TCBZ resistance. We validated this locus independently using bulk segregant analysis of F. hepatica populations and showed that it is the target of drug selection in the field. We genotyped individual parasites and tracked segregation and reassortment of SNPs to show that TCBZ resistance exhibits Mendelian inheritance and is conferred by a dominant allele. We defined gene content within this locus to pinpoint genes involved in membrane transport, (e.g. ATP-binding cassette family B, ABCB1), transmembrane signalling and signal transduction (e.g. GTP-Ras-adenylyl cyclase and EGF-like protein), DNA/RNA binding and transcriptional regulation (e.g. SANT/Myb-like DNA-binding domain protein) and drug storage and sequestration (e.g. fatty acid binding protein, FABP) as prime candidates for conferring TCBZ resistance. This study constitutes the first experimental cross and genome-wide approach for any heritable trait in F. hepatica and is key to understanding the evolution of drug resistance in Fasciola spp. to inform deployment of efficacious anthelmintic treatments in the field. The common liver fluke, Fasciola hepatica, causes disease in livestock worldwide and is a zoonosis, resulting in infection in humans in some parts of the world. The main method of treatment in both humans and animals is the drug triclabendazole (TCBZ) because of its activity against both immature and adult parasites. Although resistance to TCBZ is a substantial threat to control of the parasite, we do not know exactly how the drug acts on the parasites or which regions of the genome, or genes, are inherited by parasites that survive TCBZ treatment. Previous studies have focused on analysing genes that are assumed to be involved in drug action. Here, we took an unbiased approach and scanned the whole parasite genome from both experimental and natural infections to identify areas that respond to TCBZ exposure. We identified a small region, equating to just 0.25% of the genome from our experimental infection that is under TCBZ selection. This genomic region was also selected when naturally infected sheep were treated with TCBZ. We found that parasites surviving treatment only needed to inherit one copy of this resistance region, making it a dominant genetic trait. We showed that the resistance region encodes 30 genes and by characterising their function, we have been able to identify several genes that could confer TCBZ resistance in liver fluke. Our findings substantially advance the understanding of how liver fluke have become resistant to TCBZ and pave the way for molecular tests to detect drug resistant parasites and more effectively target treatments in both livestock and humans.
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影响因子：
4
作者：
Ranford-Cartwright LC;Mwangi JM
通讯作者：
Mwangi JM
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影响因子：
4
作者：
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通讯作者：
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影响因子：
9.6
作者：
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通讯作者：
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影响因子：
10.7
作者：
Choi, Young-Jun;Fontenla, Santiago;Mitreva, Makedonka
通讯作者：
Mitreva, Makedonka
影响因子：
2.2
作者：
BORAY, JC;CROWFOOT, PD;SARASIN, G
通讯作者：
SARASIN, G