Genetic diversity of levamisole receptor subunits in parasitic nematode species and abbreviated transcripts associated with resistance

Abstract

The candidate gene strategy developed in this study revealed an unexpectedly high diversity of L-AChR subunits specific to the trichostrongylid parasites that are a principal target for the drug LEV. Abbreviated variants, predicted to produce nonfunctional unc-63, were associated with LEV resistance. This study contributes significantly to a better understanding of LEV receptor constitution in parasitic nematodes and highlights the putative role of aberrant mRNA encoding L-AChR subunits in LEV resistance.

Contribution of Subunits toCaenorhabditis elegansLevamisole-Sensitive Nicotinic Receptor Function

“…It is noteworthy that the LEV-8 subunit has not been detected in Trichostrongylid parasites, and ACR-8 is the candidate to replace it in L-AChRs Neveu et al, 2010). Because this receptor constitutes the target of levamisole, ACR-8 may be involved in the molecular mechanisms leading to levamisole-resistance acquisition.…”

“…Nematode parasites cause substantial mortality and morbidity in the human population and losses in livestock and domestic animals. The free-living nematode C. elegans is a valuable tool for the study of anthelmintic targets because it shares physiological and pharmacological characteristics with parasitic nematodes, and it is sensitive to most anthelmintic drugs (Jones et al, 2005;Neveu et al, 2010). C. elegans has also emerged as a useful model organism for studying human neuromuscular diseases and for drug testing (Jones et al, 2005(Jones et al, , 2011.…”

Molecular diagnosis of infections and resistance in veterinary and human parasites

“…levamisole, pyrantel) resistance are very encouraging (Snabel et al, 2000;Martin and Robertson, 2007;Neveu et al, 2007Neveu et al, , 2010Fauvin et al, 2010). Some progress has been made toward identifying markers for macrocyclic lactone resistance (Njue and Prichard, 2004;Prichard and Roulet, 2007;De Mottier and Prichard, 2008;Beech et al, 2010), but the phenomenon appears to be complex, and perhaps to vary between species.…”

The role of drug efflux systems in anthelmintic resistance in parasitic nematodes

“…Further research showed that resistance to levamisole is associated with a spliced variant of the acr-8 gene, referred to as Hco-acr-8b which showed elevated expression in resistant worms and was undetectable in susceptible worms (Williamson et al, 2011). Neveu et al (2010) reported the presence of four paralogues of the gene . These observations suggest that the LEV receptor of some parasitic nematodes may not be the same as those found in C.…”

“…Studies conducted on the pig nematode, Oesophagostomum dentatum, involving different members of this class including levamisole and pyrantel showed that there was a lower percentage of opened ionchannels in resistant worms compared to the counterparts, suggesting an increased desensitization of drug receptors in resistant isolates (Robertson et al, 1999(Robertson et al, , 2000. Neveu et al (2010) (Boulin et al, 2011). Further research showed that resistance to levamisole is associated with a spliced variant of the acr-8 gene, referred to as Hco-acr-8b which showed elevated expression in resistant worms and was undetectable in susceptible worms (Williamson et al, 2011).…”