Jouffroy, S. | bioRxiv Science

bioRxiv2026

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.

genomics↗

bioRxiv2024

Larval motility assay using WMicrotracker: a high throughput test to discriminate between resistance and susceptibility to anthelmintic drugs in nematodes

Grazing ruminants suffer from various helminth infections particularly those caused by gastrointestinal nematode (GIN) parasites, which have a considerable impact on their welfare and productivity. Treatment predominantly relies on macrocyclic lactone (ML) anthelmintics, but their widespread application has led to the emergence of drug-resistant parasite populations worldwide. The standard method for detecting resistance, the Faecal Egg Count Reduction Test (FECRT), is susceptible to misinterpretation, leading to flawed management decisions that undermine parasite control efforts. Thus, there is a pressing need for robust resistance detection methods in field parasites. We investigated the potential of the WMicrotrackerTM (WMi) motility assay, previously unexplored in ML resistance assessment. The assay first compared ivermectin (IVM) susceptibility among wild-type Bristol N2 (N2B), IVM-selected (IVR10), and nhr-8 loss-of-function (AE501; nhr8(ok186)) Caenorhabditis elegans strains. Dose-response curves indicated differences in IVM susceptibility among strains, with IVR10 exhibiting a 2.12-fold decrease in sensitivity compared to N2B. Cross-resistance between IVM, moxidectin (MOX), and eprinomectin (EPR) was explored, demonstrating reduced susceptibility in IVR10 across all drugs compared to N2B. Further investigation was conducted using Haemonchus contortus (H. contortus) to assess the assays applicability in discriminating susceptible from resistant isolates. Results revealed significant differences in drug potency between susceptible and resistant isolates, with MOX demonstrating the highest efficacy. Resistance factors (RF) highlighted the substantial resistance of the resistant isolate to EPR. The motility assay effectively discriminated susceptible from resistant isolates in both C. elegans and H. contortus. Our findings demonstrate, for the first time, the relevance of the motility assay by WMi as a functional indicator of resistance in nematodes, offering a promising avenue for detecting resistance to MLs. This research sheds light on a novel approach for monitoring drug resistance, vital for effective parasite management strategies.

pharmacology and toxicology↗