Abstract

Like other pathogens, parasitic helminths can rapidly evolve resistance to drug treatment. Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to tracking its spread and improving the efficacy and sustainability of parasite control. Here, we use an in vivo genetic cross between drug-susceptible and multi-drug-resistant strains of Haemonchus contortus in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies new alleles for resistance to benzimidazoles and levamisole and implicates the transcription factor cky-1 in ivermectin resistance. This gene is within a locus under selection in ivermectin-resistant populations worldwide; expression analyses and functional validation using knockdown experiments support that cky-1 is associated with ivermectin survival. Our work demonstrates the feasibility of high-resolution forward genetics in a parasitic nematode and identifies variants for the development of molecular diagnostics to combat drug resistance in the field.

Data availability

Raw sequencing data for this study are outlined in table S1 and are archived under the ENA study accession PRJEB4207. The H. contortus genome assembly and manually curated annotation resources are publicly available at https://parasite.wormbase.org/Haemonchus_contortus_prjeb506/Info/Index/. The code used to generate and analyse data and to plot figures can be found at https://github.com/stephenrdoyle/hcontortus_X-QTL.