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

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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. **