Moredun Research Institute, Pentlands Science Park, Bush Loan, Edinburgh, EH26 0PZ, United Kingdom; Institute of Biodiversity Animal Health and Comparative Medicine, University of Glasgow, Bearsden Road, Glasgow, G61 1QH, United Kingdom.
Institute of Biodiversity Animal Health and Comparative Medicine, University of Glasgow, Bearsden Road, Glasgow, G61 1QH, United Kingdom.
Int J Parasitol Drugs Drug Resist. 2018 Apr;8(1):70-80. doi: 10.1016/j.ijpddr.2018.01.004. Epub 2018 Jan 31.
The Teladorsagia circumcincta P-glycoprotein-9 (Tci-pgp-9) gene has previously been implicated in multiple-anthelmintic resistance in this parasite. Here we further characterise genetic diversity in Tci-pgp-9 and its possible role in ivermectin (IVM) and multi-drug resistance using two UK field isolates of T. circumcincta, one susceptible to anthelmintics (MTci2) and the other resistant to most available anthelmintics including IVM (MTci5). A comparison of full-length Tci-pgp-9 cDNA transcripts from the MTci2 and MTci5 isolates (∼3.8 kb in both cases) indicated that they shared 95.6% and 99.5% identity at the nucleotide and amino acid levels, respectively. Nine non-synonymous SNPs were found in the MTci5 sequences relative to their MTci2 counterparts. Twelve genomic sequence variants of the first internucleotide binding domain of Tci-pgp-9 were identified and up to 10 of these were present in some individual worms, strongly supporting previous evidence that amplification of this gene has occurred in T. circumcincta. On average, fewer distinct sequence variants of Tci-pgp-9 were present in individual worms of the MTci5 isolate than in those of the MTci2 isolate. A further reduction in the number of sequence variants was observed in individuals derived from an IVM-treated sub-population of MTci5. These findings suggest that Tci-pgp-9 was under purifying selection in the face of IVM treatment in T. circumcincta, with some sequence variants being selected against.
先前的研究表明，细颈线虫 P 糖蛋白-9（Tci-pgp-9）基因与该寄生虫的多种抗寄生虫药物耐药性有关。在这里，我们使用来自两个英国田间分离株的细颈线虫进一步描述了 Tci-pgp-9 的遗传多样性及其在伊维菌素（IVM）和多药耐药性中的可能作用，其中一个对驱虫药敏感（MTci2），另一个对包括 IVM 在内的大多数可用驱虫药耐药（MTci5）。对 MTci2 和 MTci5 分离株的全长 Tci-pgp-9 cDNA 转录本进行比较（在两种情况下均约为 3.8kb）表明，它们在核苷酸和氨基酸水平上分别具有 95.6%和 99.5%的同源性。在 MTci5 序列中发现了 9 个非同义 SNP，相对于其 MTci2 对应物。鉴定了 Tci-pgp-9 第一内含子结合域的 12 个基因组序列变体，其中多达 10 个存在于某些个体蠕虫中，这强烈支持了先前的证据，即该基因的扩增发生在细颈线虫中。平均而言，MTci5 分离株中单个蠕虫的 Tci-pgp-9 不同序列变体少于 MTci2 分离株。在来自 MTci5 的 IVM 处理亚群的个体中观察到序列变体数量进一步减少。这些发现表明，在细颈线虫中，Tci-pgp-9 在面对 IVM 治疗时受到了净化选择，一些序列变体被选择淘汰。
