Variation in anthelmintic responses are driven by genetic differences among diverse C. elegans strains

Treatment of parasitic nematode infections in humans and livestock relies on a small arsenal of anthelmintic drugs that have historically reduced parasite burdens. However, anthelmintic resistance (AR) is increasing, and little is known about the molecular and genetic causes of resistance for most drugs. The free-living roundworm Caenorhabditis elegans has proven to be a tractable model to understand AR, where studies have led to the identification of molecular targets of all major anthelmintic drug classes. Here, we used genetically diverse C. elegans strains to perform dose-response analyses across 26 anthelmintic drugs that represent the three major anthelmintic drug classes (benzimidazoles, macrocyclic lactones, and nicotinic acetylcholine receptor agonists) in addition to seven other anthelmintic classes. First, we found that C. elegans strains displayed significant variation in anthelmintic responses across drug classes. Dose-response trends within a drug class showed that the C. elegans strains elicited similar responses within the benzimidazoles but variable responses in the macrocyclic lactones and nicotinic acetylcholine receptor agonists. Next, we compared the effective concentration estimates to induce a 10% maximal response (EC10) and slope estimates of each dose-response curve of each strain to the reference strain, N2, which enabled the identification of anthelmintics with population-wide differences to understand how genetics contribute to AR. Because genetically diverse strains displayed differential susceptibilities within and across anthelmintics, we show that C. elegans is a useful model for screening potential nematicides. Third, we quantified the heritability of responses to each anthelmintic and observed a significant correlation between exposure closest to the EC10 and the exposure that exhibited the most heritable responses. Heritable genetic variation can be explained by strain-specific anthelmintic responses within and across drug classes. These results suggest drugs to prioritize in genome-wide association studies, which will enable the identification of AR genes. ### Competing Interest Statement The authors have declared no competing interest.