Investigating the acetylcholine receptor diversity in parasitic nematodes as potential targets for the development of novel anthelmintics
Résumé
Parasitic nematode infections of humans and animals are world-wide. In humans, they cause disease and perpetuate a cycle of poverty. In animals, the parasites cause welfare problems and production loss. In developing countries, the debilitating effect of nematode parasites in school children limits their education, and in adults reduces productivity. These two factors, along with the production loss associated with nematode infections of animals that affects human nutrition, sustain poverty. Treatment and prophylaxis of these parasites requires the use of anthelmintic drugs. Here, we employ the Xenopus oocyte expression system to investigate the diversity of anthelmintic receptors in the parasitic nematode Oesophagostomum dentatum. We demonstrate effects of the ‘novel’ anthelmintics tribendimidine and derquantel on these reconstituted receptors, revealing, for the first time, the subunits that make up a tribendimidine- and derquantel-sensitive receptor from a parasitic nematode. We show that the receptor structure and pharmacology can be plastic, and depends on subunit composition and stoichiometry. The factors that affect the diversity of the receptor may contribute to anthelmintic resistance. Our results demonstrate the presence of acetylcholine receptor subtypes that may serve as anthelmintic targets and suggest that pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms.