Deciphering Ivermectin Resistance: Contribution of P-Glycoproteins in Loss-of-Function Strains of Ivermectin-Resistant Caenorhabditis elegans
Résumé
Infection of grazing ruminants by helminth parasites affects animal welfare and leads to massive economic losses. The fight against these parasites relies on the use of powerful anthelmintic (AH) drugs, such as Ivermectin (IVM). AH efficiency is being undermined by the development of drug resistance among the targeted population. Resistance to IVM is complex, involving polygenic mechanisms, including the up regulation of detoxification systems. Notably, the nematode model Caenorhabditis elegans developed by selection on IVM pressure and resistant to IVM (IVR10), was previously shown to overexpress genes encoding P-glycoproteins (PGPs) and cytochrome P450 enzymes (CYP450s). Using CRISPR-Cas9 genome editing technique, we have engineered original stable IVR10 strains, deleted individually for the most overexpressed pgps and one cyp450 gene. We have then studied the consequences of loss of function of either PGP or CYP450 on IVM susceptibility. We compared IVM efficacy in wild-type, IVR10, and the different IVR10 knock-out strains, using several phenotypes such as development, motility or pharyngeal pumping. Among several PGPs and CYP studied, we identified PGP-9 as an essential player in the preservation of the resistance phenotype in the IVR10 strain, providing a potentially relevant target to improve IVM-based treatments. Following this discovery, using a novel IVM fluorescent probe and rescue strains, we aim to study drug distribution in the nematode to better understand the relationship between PGP-9 and IVM resistance. Acknowledgements: This work is supported by grant N° ANR-21-CES35-004 “Fluo-RES” from the Agence Nationale de la Recherche.