Natural variation in Caenorhabditis elegans responses to the anthelmintic emodepside

Abstract

Treatment of parasitic nematode infections depends primarily on the use of anthelmintics. However, this drug arsenal is limited, and resistance against most anthelmintics is widespread. Emodepside is a new anthelmintic drug effective against gastrointestinal and filarial nematodes. Nematodes that are resistant to other anthelmintic drug classes are susceptible to emodepside, indicating that the emodepside mode of action is distinct from previous anthelmintics. The laboratory-adapted Caenorhabditis elegans strain N2 is sensitive to emodepside, and genetic selection and in vitro experiments implicated slo-1, a BK potassium channel gene, in emodepside mode of action. In an effort to understand how natural populations will respond to emodepside, we measured brood sizes and developmental rates of wild C. elegans strains after exposure to the drug and found natural variation across the species. Some of the observed variation in C. elegans emodepside responses correlates with amino acid substitutions in slo-1, but genetic mechanisms other than slo-1 coding variants likely underlie emodepside resistance in wild C. elegans strains. Additionally, the assayed strains have higher offspring production in low concentrations of emodepside (a hormetic effect), which could impact treatment strategies when parasites are underdosed. We find that natural variation affects emodepside sensitivity, supporting the suitability of C. elegans as a model system to study emodepside responses across natural nematode populations. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/425329v2_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1139cf4org.highwire.dtl.DTLVardef@a56a30org.highwire.dtl.DTLVardef@1de8b2forg.highwire.dtl.DTLVardef@183e4a6_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIEmodepside responses vary across the C. elegans species. C_LIO_LIWild strains of C. elegans model natural differences in parasite emodepside responses. C_LIO_LIVariation in the emodepside target slo-1 and other loci correlate with resistance. C_LIO_LILow doses of emodepside cause a hormetic effect on offspring production. C_LI