Sex-biased transcriptional rewiring of neuronal circuits associated with eprinomectin resistance in Haemonchus contortus

Anthelmintic resistance poses a critical threat to livestock health, with clinical failures of eprinomectin and other macrocyclic lactones documented in the gastrointestinal parasite Haemonchus contortus worldwide. We performed whole-genome Pool-seq of larvae and RNA-seq on adult male and female worms from five phenotypically characterised isolates - two eprinomectin-susceptible and three resistant - from dairy sheep in Southwest France. We identified a conserved macrocyclic lactone resistance locus on chromosome 5 and a putatively eprinomectin-specific locus on chromosome 4, alongside sex-specific transcriptomic responses linking genomic selection signatures to transcriptional phenotype. Predicted functions of selected and differentially expressed genes support reorganisation of neuronal circuits in drug responsiveness, including the kynurenine pathway producing neuroactive metabolites, further supported by quinolinic acid potentiating eprinomectin efficacy in larval assays. Despite geographic proximity, resistance appears to have evolved independently across farms. Together, these findings reveal a complex genetic architecture underlying eprinomectin resistance with implications for targeted diagnostics and resistance management.