O. dentatum: a model for resistance to levamisole
Résumé
Tractable models are required to study anthelmintic resistance in the laboratory. Although C. elegans is a very useful model, it is not a parasitic nematode and there are important difference between this Clade V nematode and other Clade V parasitic nematodes. For a number of years we have worked with levamisole-sensitive and levamisole-resistant isolates of the Clade V nematode 0. dentatum. This GI nematode is relatively easily maintained by passage through pigs and the adult female is suitable for electrophysiology. Under patch-clamp, we had found that the levamisole activated-receptor channels were not homogenous and could be separated into 4 different subtypes; one of the subtypes (G35) was not present in the resistant isolate (Robertson et al. 1999). We have pursed the 0. dentatum model further using molecular techniques to expressing levamisole receptor subunits Xenopus oocytes. Here we report our success, identifying orthologous genes of the levamisole receptor of C. elegans: unc-29, unc-63, unc-38 and acr-8 from isolates of levamisole-sensitive and levamisole-resistant 0. dentatum. Abbreviated transcripts of Ode-ACR-8 AChR subunits were detected in resistant isolates. We have used the Xenopus laevis oocyte expression system, and interestingly have observed four different functional receptor subtypes following Xenopus oocyte injection of four different combinations of these O. dentatum AChR subunits. Each subunit appears contribute a critical pharmacological role and lack of Ode-ACR-8 reduces sensitivity to levamisole. We are continuing these studies and intend to examine other important nematode parasites in different Clades.