Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
Int J Parasitol. 2011 Aug 1;41(9):951-7. doi: 10.1016/j.ijpara.2011.04.003. Epub 2011 Jun 1.
Ivermectin (IVM) resistance is an emerging problem for the control of gastrointestinal nematodes of cattle such as Cooperia oncophora and Ostertagia ostertagi. Although there is still a poor understanding of the molecular basis of macrocyclic lactone (ML)-resistance, it is clear that IVM exerts its activity by binding to glutamate-gated chloride (GluCl) channels within the parasite's neuromuscular system. One of the GluCl genes (avr-14) encodes, via alternative splicing, two subunits, AVR-14A and AVR-14B; the latter is suggested to be the main target for IVM. The genomic DNA (gDNA) sequence of avr-14 in C. oncophora contains 21 exons separated by 20 introns and spans approximately 10 kb of gDNA. Intron 13 contains a sequence with high homology to a mammalian mariner transposase. The L256F polymorphism in the avr-14 gene, which was shown to be associated with IVM resistance in a UK isolate of C. oncophora, was not found in the IVM-resistant C. oncophora and O. ostertagi isolates investigated in this study. However, genetic analyses on C. oncophora indicated a loss in allelic diversity of the avr-14 gene in the resistant isolates compared with the susceptible isolate. This suggests that the avr-14 gene, or another genetically linked locus, is under selection in these Belgian C. oncophora isolates. Comparison of the full-length avr-14B coding sequence in the susceptible and resistant C. oncophora isolates did not show any polymorphisms specifically linked to IVM resistance, although a decrease in the number of avr-14B isoforms was observed in the resistant isolates compared with the susceptible one. Measuring the transcription levels of avr-14B in adult male and female C. oncophora and O. ostertagi worms showed significantly lower levels in resistant worms compared with susceptible ones. Whether the down-regulation of this IVM target actually contributes to the resistance mechanism in these worms remains unclear.
伊维菌素 (IVM) 耐药性是牛胃肠道线虫（如旋毛虫和奥斯特拉格线虫）控制的一个新出现的问题。尽管人们对大环内酯类 (ML) 耐药性的分子基础仍知之甚少，但很明显，IVM 通过与寄生虫的神经肌肉系统中的谷氨酸门控氯通道 (GluCl) 结合发挥其作用。GluCl 基因之一 (avr-14) 通过选择性剪接编码两个亚基，AVR-14A 和 AVR-14B；后者被认为是 IVM 的主要靶标。旋毛虫的 avr-14 的基因组 DNA (gDNA) 序列包含 21 个外显子和 20 个内含子，跨越约 10kb 的 gDNA。内含子 13 包含一段与哺乳动物 mariner 转座酶具有高度同源性的序列。在本研究中，未发现与英国旋毛虫分离株相关的 IVM 耐药性的 avr-14 基因中的 L256F 多态性，也未发现 IVM 耐药的旋毛虫和奥斯特拉格线虫分离株存在该多态性。然而，旋毛虫的遗传分析表明，与敏感分离株相比，耐药分离株中 avr-14 基因的等位基因多样性丧失。这表明，avr-14 基因或另一个遗传上相关的基因座在这些比利时旋毛虫分离株中受到选择。比较敏感和耐药旋毛虫分离株的全长 avr-14B 编码序列，未发现与 IVM 耐药性特异性相关的多态性，尽管与敏感分离株相比，耐药分离株中 avr-14B 同工型的数量减少。测量成年雄性和雌性旋毛虫和奥斯特拉格线虫蠕虫中 avr-14B 的转录水平，发现耐药蠕虫中的水平明显低于敏感蠕虫。这种 IVM 靶标的下调是否实际上有助于这些蠕虫的耐药机制尚不清楚。
