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;仅牛肉就超过30 B美元/年。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%的牛群被大环内酯（ML）抗性线虫寄生，加拿大的情况也类似。线虫寄生虫的失控，将严重影响动物生产和福利。我们需要了解抗性的机制和遗传学（i）开发敏感的抗性测试，（ii）防止高水平抗性，（iii）管理现有抗性，（iv）克服抗性。 目的：1.比较秀丽隐杆线虫和捻转血矛线虫敏感和抗药性模型种群的遗传和表型特征。 2.评价田间H.以确定是否有类似的机制运作。 调查其他重要寄生虫是否也存在类似的机制，例如，牛体内的瘤孢古柏线虫。3.利用分子标记评估加拿大牛和绵羊的抗性水平。 4.评估阻力的适应度成本。 5.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：为了了解已充分表征的ML敏感和抗性模式线虫群体的遗传变化，C。elegans和H.扭曲我们有C的种群。通过暴露于MLS来选择抗性的线虫。我们发现了端足类感觉神经元的缺陷。我们在抗ML的H.扭曲这被追溯到这两个物种的dyf-7基因。然而，对更多的ML耐药C. elegans和H. contortus揭示了影响两栖类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耐药性可能出现在2个步骤，最初的浓度驱虫剂在神经元中可能会降低过表达的ABC外排泵，这是其次是改变两栖动物形态的变化。我们推测，联合作用降低了神经元中离子通道受体的ML水平。这将为我们在抗性田间种群的后续研究提供信息。这是开发耐药性分子诊断的重要一步。我们将集中在少数经济上重要的寄生虫和最重要的驱虫药在加拿大，ML。将评估宿主和自由生活阶段的一般健康状况。了解抗性和适合度成本的机制和遗传学对于制定控制线虫寄生虫而不选择抗性或失去控制的管理策略至关重要。 影响：在加拿大，耐药性是一个需要通过了解机制和开发新的诊断方法，管理策略和优秀的HQP培训来解决的问题。

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.