Abstract
Monepantel is a member of the recently identified class of anthelmintics known as the amino-acetonitrile derivatives (AADs). Monepantel controls all major gastro-intestinal nematodes in sheep including those that are resistant to the classical anthelmintics. Previous studies have shown that the Caenorhabditis elegans acr-23 and the Haemonchus contortus Hco-mptl-1 genes may be prominent targets of monepantel. With this discovery it became possible to investigate the mode of action of monepantel in nematodes at the molecular level. In the present study, we show that a C. elegans mutant acr-23 strain is fully rescued by expressing the wild-type acr-23 gene. Moreover, we present a new mutant allele, and characterize acr-23 alleles genetically. We also show that acr-23 is expressed in body wall muscle cells, and provide therefore a possible explanation for the paralysis caused by monepantel. Furthermore, genetic evidence suggests that the chaperone RIC-3 is required for expression of full monepantel resistance. Finally, we present reconstitution of the C. elegans ACR-23 receptor in Xenopus laevis oocytes and provide direct evidence of its modulation by monepantel. Conversely, co-injection of the chaperone RIC-3 had no impact for channel reconstitution in X. laevis oocytes. These results reinforce the involvement of the ACR-23 family in the mode of action of monepantel and advance our understanding of this new class of anthelmintics.
Highlights
Parasitic infections by nematodes represent a serious threat to the health of humans, companion animals and livestock
ACR-23 is expressed in body wall muscles In order to identify tissues that express ACR-23 and are targeted by monepantel, we generated transgenic C. elegans that produce an ACR-23::GFP fusion protein driven by the acr-23 promoter
Wild-type ACR-23 is targeted by monepantel The implication of DEG-3 subfamily channels in sensitivity to monepantel is based on mutations found in nematodes that are resistant to amino-acetonitrile derivatives (AADs) [2,4,20]
Summary
Parasitic infections by nematodes represent a serious threat to the health of humans, companion animals and livestock. To investigate the molecular mode of action of AAD compounds, a genetic screen has been performed in the nonparasitic nematode Caenorhabditis elegans, which is amenable to genetic analyses [2] This screen led to the identification of 44 mutant alleles. The search for parasitic nematodes resistant to monepantel has led to the identification of Hco-mptl-1, which is disrupted in monepantel-resistant strains of the parasitic nematode Haemonchus contortus [2,4] This screen was carried out in natural hosts of this roundworm and confirms that a subunit from the DEG-3 subfamily of receptors represents a major target for monepantel [4]. To date no molecular analysis has been carried out It is not known if acr-23 is solely responsible for the resistance to the AADs and how the ACR-23 protein responds to monepantel.
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