Anthelmintic resistance in parasitic nematodes

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Anthelmintic drugs are an essential component of livestock production throughout the world although rising resistance poses a serious threat to their use. Detailing specific molecular changes that cause resistance can be used to find effective alternatives. Many anthelmintics target ligand-gated ion-channels (LGIC) in nematode neuromusculature and can be used to probe basic biology of the nematode nervous system, providing insight into nerve impulse transmission in general. To be relevant in the field we also need to understand mechanisms by which resistance evolves and spreads and so devise more effective drug application and animal management programs. Genome projects for 11 nematode parasites will be completed within 10 years, opening new analysis techniques. To make effective use of these we must understand parasite genetics. My research program is to determine specific mechanisms of resistance at the molecular level and characterize parasite genetics to understand the evolution of resistance. I previously identified two LGICs altered in macrocyclic lactone resistant Haemonchus contortus, a widespread model parasite of sheep and goats. Their expression pattern and pharmacology explain the physiological effects of the drug and changes in the resistant forms alter the parasite response to drug exposure in vivo. I have identified about 85 LGIC genes in the partial genome sequence of H. contortus and full or partial cDNAs are known for 30 of these. For the first part of my research program I propose to further characterize functional changes in macrocyclic lactone resistant LGICs and isolate the remaining LGICs from H. contortus. The function of specific LGICs linked with resistance to levamisole and the newly reported amido acetonitrile anthelmintics will be examined. For the second I propose to determine how genes act in combination to effect resistance and to characterize genetic linkage between genes. This will provide information on the function of LGICs in general and specific changes that cause macrocyclic lactone resistance; extend our knowledge of an important pathogen of livestock and possibly identify new drug targets; lay a foundation for LGIC research and the post-genomic era analysis of resistance in H. contortus.