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Using a health-rating system to evaluate the usefulness of Caenorhabditis elegans as a model for anthelmintic study.

ABSTRACT: Soil-transmitted helminths (STHs) are intestinal parasitic nematodes that infect humans, and are transmitted through contaminated soil. These nematodes include the large roundworm (Ascaris lumbricoides), whipworm (Trichuris trichiura), and hookworm (Ancylostoma ceylanicum, Ancylostoma duodenale, and Necator americanus). Nearly 1.5 billion people (~24% of the population) worldwide are infected with at least one species of these parasites, burdening the poor, in particular, children and pregnant women. To combat these diseases, the WHO only recognizes four anthelmintic drugs, including the preferred drug, albendazole, for mass drug administration (MDA). These four drugs have a total of two different mechanisms of action, and, as expected, resistance has been observed. This problem calls for new drugs with different mechanisms of action. Although there is precedence for the use of Caenorhabditis elegans (C. elegans), a free-living nematode, as a model for drug screening and anthelmintic testing, their usefulness for such anthelmintic study is not clear as past research has shown that C. elegans did not show a strong response to albendazole, the MDA drug of choice, in comparison with various STHs under similar treatment. To further examine if C. elegans has the potential to be a good model organism for anthelmintic drug study, we employed a health rating scale in order to tease out potential effects of albendazole, and other anthelmintics, that may have been missed using a binary, dead/alive scale. Using the health-rating scale we found that although the worms may have not been dying, they were sick, showing dose responses to anthelmintic drugs, including albendazole, reinforcing C. elegans as a useful model for anthelmintic study.

SUBMITTER: Weaver KJ

PROVIDER: S-EPMC5478128 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Using a health-rating system to evaluate the usefulness of Caenorhabditis elegans as a model for anthelmintic study.

Weaver Kathryn J KJ May Cassandra J CJ Ellis Brian L BL

PloS one 20170620 6

Soil-transmitted helminths (STHs) are intestinal parasitic nematodes that infect humans, and are transmitted through contaminated soil. These nematodes include the large roundworm (Ascaris lumbricoides), whipworm (Trichuris trichiura), and hookworm (Ancylostoma ceylanicum, Ancylostoma duodenale, and Necator americanus). Nearly 1.5 billion people (~24% of the population) worldwide are infected with at least one species of these parasites, burdening the poor, in particular, children and pregnant w ...[more]

PMID: 28632749

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Project description:Parasitic nematodes are major human and agricultural pests, and benzimidazoles are amongst the most important broad-spectrum anthelmintic drug class used for their control. Benzimidazole resistance is now widespread in many species of parasitic nematodes in livestock globally and an emerging concern for the sustainable control of human soil-transmitted helminths. β-tubulin is the major benzimidazole target, although other genes may influence resistance. Among the 6 Caenorhabditis elegans β-tubulin genes, loss of ben-1 causes resistance without other apparent defects. Here, we explored the genetics of C. elegans β-tubulin genes in relation to the response to the benzimidazole derivative albendazole. The most highly expressed β-tubulin isotypes, encoded by tbb-1 and tbb-2, were known to be redundant with each other for viability, and their products are predicted not to bind benzimidazoles. We found that tbb-2 mutants, and to a lesser extent tbb-1 mutants, were hypersensitive to albendazole. The double mutant tbb-2 ben-1 is uncoordinated and short, resembling the wild type exposed to albendazole, but the tbb-1 ben-1 double mutant did not show the same phenotypes. These results suggest that tbb-2 is a modifier of albendazole sensitivity. To better understand how BEN-1 mutates to cause benzimidazole resistance, we isolated mutants resistant to albendazole and found that 15 of 16 mutations occurred in the ben-1 coding region. Mutations ranged from likely nulls to hypomorphs, and several corresponded to residues that cause resistance in other organisms. Null alleles of ben-1 are albendazole-resistant and BEN-1 shows high sequence identity with tubulins from other organisms, suggesting that many amino acid changes could cause resistance. However, our results suggest that missense mutations conferring resistance are not evenly distributed across all possible conserved sites. Independent of their roles in benzimidazole resistance, tbb-1 and tbb-2 may have specialized functions as null mutants of tbb-1 or tbb-2 were cold or heat sensitive, respectively.

Project description:The anthelmintic treatment of nematode infections remains the pillar of worm control in both human and veterinary medicine. Since control is threatened by the appearance of drug resistant nematodes, there is a need to develop novel compounds, among which phytochemicals constitute potential anthelmintic agents. Caenorhabditis elegans has been pivotal in anthelmintic drug discovery and in revealing mechanisms of drug action and resistance. By using C. elegans, we here revealed the anthelmintic actions of three plant terpenoids -thymol, carvacrol and eugenol- at the behavioral level. Terpenoids produce a rapid paralysis of worms with a potency rank order carvacrol > thymol > eugenol. In addition to their paralyzing activity, they also inhibit egg hatching, which would, in turn, lead to a broader anthelmintic spectrum of activity. To identify drug targets, we performed an in vivo screening of selected strains carrying mutations in receptors involved in worm locomotion for determining resistance to the paralyzing effect of terpenoids. The assays revealed that two Cys-loop receptors with key roles in worm locomotion -Levamisole sensitive nicotinic receptor (L-AChR) and GABA(A) (UNC-49) receptor- are involved in the paralyzing effects of terpenoids. To decipher the mechanism by which terpenoids affect these receptors, we performed electrophysiological studies using a primary culture of C. elegans L1 muscle cells. Whole cell recordings from L1 cells demonstrated that terpenoids decrease macroscopic responses of L-AChR and UNC-49 receptor to their endogenous agonists, thus acting as inhibitors. Single-channel recordings from L-AChR revealed that terpenoids decrease the frequency of opening events, probably by acting as negative allosteric modulators. The fact that terpenoids act at different receptors may have important advantages regarding efficacy and development of resistance. Thus, our findings give support to the use of terpenoids as either an alternative or a complementary anthelmintic strategy to overcome the ever-increasing resistance of parasites to classical anthelmintic drugs.

Dataset Information

Using a health-rating system to evaluate the usefulness of Caenorhabditis elegans as a model for anthelmintic study.

Publications

Using a health-rating system to evaluate the usefulness of Caenorhabditis elegans as a model for anthelmintic study.

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