Anthelmintic resistance in animal parasitic nematodes: Mechanisms, genetics, diagnosis, extent, fitness cost, prevention and management

加拿大的畜牧业很重要；单是牛肉一年就有300亿美元。线虫寄生虫使收益减少7%。寄生虫控制依赖于驱虫药。在美国，50%的牛群被抗大环内酯（ML）的线虫寄生，加拿大的情况也类似。线虫寄生虫失去控制，将严重影响动物生产和福利。我们需要了解耐药性的机制和遗传（一）开发敏感的耐药性测试，（二）防止高水平的耐药性，（三）管理现有的耐药性，（四）克服耐药性。* * * *目的:1。比较秀丽隐杆线虫和弯血蜱的易感和抗虫模型种群的遗传和表型特征。目的：评价田间弯纹夜蛾种群，以确定是否存在类似的机制。*调查其他重要寄生虫是否也存在类似的机制，例如牛体内的瘤Cooperia oncophora。3. 利用分子标记技术评估加拿大牛羊的抗性水平。评估抵抗的适应度成本。在了解抗性的基础上，制定减少抗性选择的寄生虫控制策略。****科学方法：了解模型线虫、秀丽隐杆线虫和弯曲线虫的ML易感和耐药群体的遗传变化。我们有秀丽隐杆线虫的种群选择抗性暴露于MLs。我们在两栖动物的感觉神经元中发现了一个缺陷。我们在抗ML的扭曲鼠的神经元中发现了类似的缺陷。这可以追溯到两个物种的dyf-7基因。然而，对更多的ML抗性秀丽隐杆线虫和弯曲线虫分离株的检测表明，影响两栖动物神经元形态的其他基因也可能参与其中。我们的数据表明，ML抗性可能分两个步骤产生，最初，神经元中驱虫体的浓度可能因ABC外排泵的过度表达而降低，随后发生变化，改变两栖动物的形态。我们假设这些综合作用降低了神经元离子通道受体的ML水平。这将为后续抗性田间种群的研究提供信息。这是发展耐药性分子诊断的重要一步。我们将重点关注少数经济上重要的寄生虫和加拿大最重要的驱虫动物，MLs。评估宿主和自由生活阶段的一般健康状况。了解抗性和适应成本的机制和遗传学对制定控制线虫寄生虫的管理策略具有重要意义。****影响：在加拿大，耐药性是一个问题，需要通过理解机制、开发新的诊断方法、管理策略和优秀的HQP培训来采用新的方法。**

Canada's livestock industries are important; beef alone >$30 b/year. Nematode parasites reduce returns by 7%. Parasite control depends on anthelmintics. In USA, 50% of the cattle herds are parasitized with macrocyclic lactone (ML) resistant nematodes and the situation appears similar in Canada. A loss of control of nematode parasites, will seriously impact animal production and welfare. We need to understand mechanisms and genetics of resistance (i) to develop sensitive tests for resistance, (ii) to prevent high level resistance, (iii) manage existing resistance, and (iv) overcome resistance.****Objectives: 1. To compare the genetic and phenotypic profiles of susceptible and anthelmintic resistant model populations of Caenorhabditis elegans and Haemonchus contortus.*2. To evaluate field populations of H. contortus to determine whether similar mechanisms operate.*To investigate whether similar mechanisms occur in other important parasites, e.g., Cooperia oncophora in cattle. 3. To evaluate the level of resistance in Canadian cattle and sheep, using molecular markers.*4. To evaluate fitness cost of resistance.*5. Based on understanding resistance, to develop parasite control strategies which reduce selection for resistance.****Scientific approach: To understand the genetic changes in well characterized ML susceptible and resistant populations of model nematodes, C. elegans and H. contortus. We have populations of C. elegans selected for resistance by exposure to MLs. We find a defect in sensory neurons in the amphids. We see a similar defect in neurons in ML resistant H. contortus. This was traced to the dyf-7 gene in both species. However, examination of more isolates of ML resistant C. elegans and H. contortus has revealed that other genes which affect amphid neuron morphology may also be involved. Our data suggests ML resistance may arise in 2 steps, initially the concentration of the anthelmintic in the neurons may be lowered by overexpression of ABC efflux pumps and this is followed by changes which alter amphid morphology. We hypothesize the combined effects reduce the ML level at ion channel receptors in neurons. This will provide us with information for subsequent studies in resistant field populations. This is an essential step in developing molecular diagnostics for resistance. We will focus on a small number of economically important parasites and the most important anthelmintics in Canada, the MLs. Assessments of general fitness in the host and in free-living stages will be assessed. Understanding the mechanisms and genetics of resistance and fitness cost are critical for developing management strategies for controlling nematode parasites without selection for resistance or loss of control.****Impact: In Canada resistance is a problem requiring novel approaches by understanding the mechanisms and developing novel diagnostics, management strategies and excellent HQP training. **