Caenorhabditis elegans in anthelmintic research - Old model, new perspectives

Abstract

For more than four decades, the free-living nematode Caenorhabditis elegans has been extensively used in anthelmintic research. Classic genetic screens and heterologous expression in the C. elegans model enormously contributed to the identification and characterization of molecular targets of all major anthelmintic drug classes. Although these findings provided substantial insights into common anthelmintic mechanisms, a breakthrough in the treatment and control of parasitic nematodes is still not in sight. Instead, we are facing increasing evidence that the enormous diversity within the phylum Nematoda cannot be recapitulated by any single free-living or parasitic species and the development of novel broad-spectrum anthelmintics is not be a simple goal. In the present review, we summarize certain milestones and challenges of the C. elegans model with focus on drug target identification, anthelmintic drug discovery and identification of resistance mechanisms. Furthermore, we present new perspectives and strategies on how current progress in C. elegans research will support future anthelmintic research.

Keywords: Anthelmintic drug; Anthelmintic resistance; Caenorhabditis elegans; Mode of action; Parasitic nematode.

Graphical abstract

Fig. 1

Overview on scientific publications using Caenorhabditis elegans for anthelmintic research. The bar plot presents an overview of scientific studies that used the free-living model nematode C. elegans for anthelmintic research, sorted by the year of publication (1975–2019). Abstracts of relevant publications were collected by an automated literature search using the bibliographic databases CAB Direct (www.cabdirect.org), provided by Centre for Agriculture and Bioscience International (CABI), and EMBASE (www.emabse.com). For initial abstract extraction, terms were used that combined “C. elegans” with relevant key words, including “anthelmintic drugs”, “nematode parasite species” or “anthelmintic resistance”. The data set was manually curated to obtain a final number of 475 abstracts. For this final selection, publications were considered that included the experimental usage of C. elegans for anthelmintic drug discovery, target characterization, and mode of resistance elucidation. Moreover, selected review articles have a focus on different aspects of C. elegans in anthelmintic research. All selected abstracts are listed in Sup Table 1.

Fig. 2

The Caenorhabditis elegans natural diversity resource (CeNDR) provides insights into genetic and phenotypic variation of natural C. elegans population. (A) The map shows global origin of C. elegans strains that are available to the community through CeNDR. Overall, 249 genetically diverse strains were collected over the past 50 years by researchers and citizen-scientists from different regions and substrates all over the world. All isolated strains were cryopreserved and genome sequenced. (B) Genomic variation in anthelmintic drug targets can be queried with the CeNDR Variant Browser tool (https://www.elegansvariation.org/data/browser/). As an example, the genetic variation in the beta-tubulin gene ben-1, a major resistance gene for benzimidazoles, is shown. Genetic variants with predicted moderate (e.g. missense variants) or high effects (e.g. frame shift variants) are displayed in yellow or red, respectively. (C) CeNDR strains vary in their phenotypic response to anthelmintic drugs. As an example, the relative resistance to albendazole (ABZ) is shown (Hahnel et al., 2018). Each bar represents a single CeNDR strain, included in an ABZ exposure assay, sorted by their relative ABZ resistance. Strains that have ben-1 variants with predicted moderate or high effects are colored in yellow and red, respectively. Strains similar to the N2 reference genome with respect to the ben-1 locus are shown in grey. Distribution of strains with a ben-1 variant indicate a correlation between ben-1 and ABZ resistance in C. elegans wild isolates. (D) Phenotype and genotype data of wild isolates can be used to identify genomic regions or genes that correlate with an observed resistance phenotype. The example shows the Manhattan plot of a genome-wide association study performed to identify genetic determinants of BZ resistance in CeNDR strains (Hahnel et al., 2018). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)