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.

Natural variation inCaenorhabditis elegansresponses to the anthelmintic emodepside

“…It is unlikely that one C. elegans strain represents all possible genes and variants that contribute to emodepside sensitivity. The use of multiple isolates in drug response studies increases the likelihood of elucidating mechanisms of resistance and drug mode of action shared by multiple strains and species (Hahnel et al, 2020;Wit et al, 2020). Natural variation across the C. elegans species is archived in the C.…”

“…The free-living nematode C. elegans is a long standing model to study anthelmintic mode of action and resistance of parasitic nematodes (Geary and Thompson, 2001;Hahnel et al, 2020;Holden-Dye et al, 2014;Wit et al, 2020). The suitability of C. elegans as a model is the result of a range of attributes, including the phylogenetic relationship of C. elegans with many parasitic nematodes of human and veterinary importance, its short and direct life cycle, a wide range of genome-editing tools, and its high-quality reference genome and gene models.…”

“…It is unlikely that one C. elegans strain represents all possible genes and variants that contribute to emodepside sensitivity. The use of multiple isolates in drug response studies increases the likelihood of elucidating mechanisms of resistance and drug mode of action shared by multiple strains and species (Hahnel et al 2020; Wit, Dilks, and Andersen 2020). The natural variation across the C. elegans species is archived in the C. elegans Natural Diversity Resource (CeNDR) (Cook et al 2017) and offers a powerful approach to look for genetic variation that underlies the different responses to emodepside, as has been done for other drugs (Evans and Andersen 2020; Brady et al 2019; Hahnel et al 2018; Zamanian et al 2018; Zdraljevic et al 2019, 2017).…”

Natural variation in Caenorhabditis elegans responses to the anthelmintic emodepside

“…The above studies on emodepside mode of action and resistance in C. elegans focused on the N2 laboratory strain and mutants in that genetic background. Although C. elegans is a great model organism for parasitic nematodes ( Bürglin et al, 1998 ; Dilks et al, 2020 ; Hahnel et al, 2018 , 2020 ; Wit et al, 2020 ), studies that use only a single strain can be biased by rare variation or genetic modifiers specific to a single genetic background ( Sterken et al, 2015 ). The observation that emodepside affects multiple nematode species suggests that its mode of action is conserved throughout the phylum.…”

Behavioral fingerprints predict insecticide and anthelmintic mode of action

“…We chose C. elegans as our model system because it is small and compatible with multiwell plates and automated liquid handling. It is sensitive to anthelmintics and insecticides and has played an important role in mode of action discovery in the past 16,[18][19][20][21] .…”