Dataset Information

Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans.

ABSTRACT: Anthelmintic resistance is a major problem in livestock farming, especially of small ruminants, but our understanding of it has been limited by the difficulty in carrying out functional genetic studies on parasitic nematodes. An important nematode infecting sheep and goats is Haemonchus contortus; in many parts of the world this species is resistant to almost all the currently available drugs, including ivermectin. It is extremely polymorphic and to date it has proved impossible to relate any sequence polymorphisms to its ivermectin resistance status. Expression of candidate drug-resistance genes in Caenorhabditis elegans could provide a convenient means to study the effects of polymorphisms found in resistant parasites, but may be complicated by differences between the gene families of target and model organisms. We tested this using the glutamate-gated chloride channel (GluCl) gene family, which forms the ivermectin drug target and are candidate resistance genes. We expressed GluCl subunits from C. elegans and H. contortus in a highly resistant triple mutant C. elegans strain (DA1316) under the control of the avr-14 promoter; expression of GFP behind this promoter recapitulated the pattern previously reported for avr-14. Expression of ivermectin-sensitive subunits from both species restored drug sensitivity to transgenic worms, though some quantitative differences were noted between lines. Expression of an ivermectin-insensitive subunit, Hco-GLC-2, had no effect on drug sensitivity. Expression of a previously uncharacterised parasite-specific subunit, Hco-GLC-6, caused the transgenic worms to become ivermectin sensitive, suggesting that this subunit also encodes a GluCl that responds to the drug. These results demonstrate that both orthologous and paralogous subunits from C. elegans and H. contortus are able to rescue the ivermectin sensitivity of mutant C. elegans, though some quantitative differences were observed between transgenic lines in some assays. C. elegans is a suitable system for studying parasitic nematode genes that may be involved in drug resistance.

SUBMITTER: Glendinning SK

PROVIDER: S-EPMC3144221 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans.

Glendinning Susan K SK Buckingham Steven D SD Sattelle David B DB Wonnacott Susan S Wolstenholme Adrian J AJ

PloS one 20110726 7

Anthelmintic resistance is a major problem in livestock farming, especially of small ruminants, but our understanding of it has been limited by the difficulty in carrying out functional genetic studies on parasitic nematodes. An important nematode infecting sheep and goats is Haemonchus contortus; in many parts of the world this species is resistant to almost all the currently available drugs, including ivermectin. It is extremely polymorphic and to date it has proved impossible to relate any se ...[more]

PMID: 21818319

Similar Datasets

Project description:Simple Summary Ivermectin (IVM) is a highly effective, broad-spectrum, gold-standard antiparasitic drug that has been used extensively to control nematodes such as Haemonchus contortus. However, IVM-resistant H. contortus populations are now common throughout the world, and there is limited understanding of the mechanisms underlying IVM resistance in H. contortus. Recent studies have offered evidence that the metabolic status of bacteria significantly affects their antibiotic sensitivity and that specific metabolic characteristics are related to resistance. Thus, in the present study, we explored the metabolome of an IVM-resistant H. contortus strain and analyzed the role of metabolism in IVM resistance. These results contribute to our understanding of the mechanisms of IVM resistance in H. contortus. Abstract Resistance to anthelmintics such as ivermectin (IVM) is currently a major problem in the treatment of Haemonchus contortus, an important parasitic nematode of small ruminants. Although many advances have been made in understanding the IVM resistance mechanism, its exact mechanism remains unclear for H. contortus. Therefore, understanding the resistance mechanism becomes increasingly important for controlling haemonchosis. Recent research showed that the metabolic state of bacteria influences their susceptibility to antibiotics. However, little information is available on the roles of metabolites and metabolic pathways in IVM resistance of H. contortus. In this study, comparative analyses of the metabolomics of IVM-susceptible and -resistant adult H. contortus worms were carried out to explore the role of H. contortus metabolism in IVM resistance. In total, 705 metabolites belonging to 42 categories were detected, and 86 differential metabolites (17 upregulated and 69 downregulated) were identified in the IVM-resistant strain compared to the susceptible one. A KEGG pathway analysis showed that these 86 differential metabolites were enriched in 42 pathways that mainly included purine metabolism; the biosynthesis of amino acids; glycine, serine, and threonine metabolism; and cysteine and methionine metabolism. These results showed that amino acid metabolism may be mediated by the uptake of IVM and related with IVM resistance in H. contortus. This study contributes to our understanding of the mechanisms of IVM resistance and may provide effective approaches to manage infection by resistant strains of H. contortus.

Dataset Information

Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans.

Publications

Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets