Discovery of unique loci that underlie nematode responses to benzimidazoles

Parasitic nematodes impose a debilitating health and economic burden across much of the world. Nematode resistance to anthelmintic drugs threatens parasite control efforts in both human and veterinary medicine. Despite this threat, the genetic landscape of potential resistance mechanisms to these critical drugs remains largely unexplored. Here, we exploit natural variation in the model nematodes Caenorhabditis elegans and Caenorhabditis briggsae to discover quantitative trait loci (QTL) that control sensitivity to benzimidazoles widely used in human and animal medicine. High-throughput phenotyping of albendazole, fenbendazole, mebendazole, and thiabendazole responses in panels of recombinant lines led to the discovery of over 15 QTL in C. elegans and four QTL in C. briggsae associated with divergent responses to these anthelmintics. Many of these QTL are conserved across benzimidazole derivatives, but others show drug and dose specificity. We used near-isogenic lines to recapitulate and narrow the C. elegans albendazole QTL of largest effect and identified candidate variants correlated with the resistance phenotype. These QTL do not overlap with known benzimidazole resistance genes from parasitic nematodes and present specific new leads for the discovery of novel mechanisms of nematode benzimidazole resistance. Analyses of orthologous genes reveal significant conservation of candidate benzimidazole resistance genes in medically important parasitic nematodes. These data provide a basis for extending these approaches to other anthelmintic drug classes and a pathway towards validating new markers for anthelmintic resistance that can be deployed to improve parasite disease control. Author Summary The treatment of roundworm (nematode) infections in both humans and animals relies on a small number of anti-parasitic drugs. Resistance to these drugs has appeared in veterinary parasite populations and is a growing concern in human medicine. A better understanding of the genetic basis for parasite drug resistance can be used to help maintain the effectiveness of anti-parasitic drugs and to slow or to prevent the spread of drug resistance in parasite populations. This goal is hampered by the experimental intractability of nematode parasites. Here, we use non-parasitic model nematodes to systematically explore responses to the critical benzimidazole class of anti-parasitic compounds. Using a quantitative genetics approach, we discovered unique genomic intervals that control drug effects, and we identified differences in the genetic architectures of drug responses across compounds and doses. We were able to narrow a major-effect genomic region associated with albendazole resistance and to establish that candidate genes discovered in our genetic mappings are largely conserved in important human and animal parasites. This work provides new leads for understanding parasite drug resistance and contributes a powerful template that can be extended to other anti-parasitic drug classes.