Genomic landscape of drug response reveals mediators of anthelmintic resistance.
Genomic landscape of drug response reveals mediators of anthelmintic resistance.
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DOI：
10.1016/j.celrep.2022.111522
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发表时间：
2022-10-18
期刊：
影响因子：
8.8
通讯作者：
Cotton, James A.
中科院分区：
文献类型：
--
作者：
Doyle, Stephen R.;Laing, Roz;Bartley, David;Morrison, Alison;Holroyd, Nancy;Maitland, Kirsty;Antonopoulos, Alistair;Chaudhry, Umer;Flis, Ilona;Howell, Sue;McIntyre, Jennifer;Gilleard, John S.;Tait, Andy;Mable, Barbara;Kaplan, Ray;Sargison, Neil;Britton, Collette;Berriman, Matthew;Devaney, Eileen;Cotton, James A.
像其他病原体一样，寄生蠕虫可以迅速对药物治疗产生抗药性。了解寄生线虫抗蠕虫药物耐药性的遗传基础是跟踪其传播和提高寄生虫控制的有效性和可持续性的关键。在这里，我们使用的药物敏感和多药耐药的捻转血矛线虫菌株在一个自然的宿主-寄生虫系统的体内遗传杂交，同时映射的三个主要类别的驱虫药的耐药位点。这种方法确定了苯并咪唑类和左旋咪唑耐药的新等位基因，并暗示转录因子cky-1与伊维菌素耐药有关。该基因位于全世界伊维菌素耐药人群中选择的一个位点内;表达分析和使用敲除实验的功能验证支持cky-1与伊维菌素存活相关。我们的工作证明了高分辨率正向遗传学在寄生线虫中的可行性，并确定了用于开发分子诊断以对抗该领域耐药性的变体。高基因组多样性区分敏感和多药耐药蠕虫一个向前的遗传杂交揭示了QTL是特定的三种药物类新的因果变异定义苯并咪唑和左旋咪唑驱虫剂cky-1的表达与伊维菌素抗性在三个线虫物种Doyle等。描述了全球分布的寄生虫捻转血矛线虫的易感株和多药耐药株之间的正向遗传杂交。全基因组分析揭示了与每类药物耐药性相关的基因座，并对两类药物的新耐药等位基因进行了验证。
Like other pathogens, parasitic helminths can rapidly evolve resistance to drug treatment. Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to tracking its spread and improving the efficacy and sustainability of parasite control. Here, we use an in vivo genetic cross between drug-susceptible and multi-drug-resistant strains of Haemonchus contortus in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies new alleles for resistance to benzimidazoles and levamisole and implicates the transcription factor cky-1 in ivermectin resistance. This gene is within a locus under selection in ivermectin-resistant populations worldwide; expression analyses and functional validation using knockdown experiments support that cky-1 is associated with ivermectin survival. Our work demonstrates the feasibility of high-resolution forward genetics in a parasitic nematode and identifies variants for the development of molecular diagnostics to combat drug resistance in the field. High genomic diversity differentiates susceptible and multi-drug-resistant helminths A forward genetic cross reveals QTLs that are specific to each of three drug classes Novel causal variants are defined for benzimidazole and levamisole anthelmintics cky-1 expression is correlated with ivermectin resistance in three nematode species Doyle et al. describe a forward genetic cross between susceptible and multi-drug-resistant strains of the globally distributed parasitic worm Haemonchus contortus. Whole-genome analysis reveals loci associated with resistance to each drug class, and novel resistance alleles are validated for two classes.
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影响因子：
4.5
作者：
Choi YJ;Bisset SA;Doyle SR;Hallsworth-Pepin K;Martin J;Grant WN;Mitreva M
通讯作者：
Mitreva M
影响因子：
4
作者：
Avramenko, Russell W.;Redman, Elizabeth M.;Gilleard, John S.
通讯作者：
Gilleard, John S.
影响因子：
7.8
作者：
Luo, Shuo;Chen, Yu;Lai, Kwok-On;Arevalo, Juan Carlos;Froehner, Stanley C;Adams, Marvin E;Chao, Moses V;Ip, Nancy Y
通讯作者：
Ip, Nancy Y
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
4.4
作者：
Chevalier, Frederic D.;Valentim, Claudia L. L.;Anderson, Timothy J. C.
通讯作者：
Anderson, Timothy J. C.