Journal Article

The transcription factor NHR-8: A new target to increase ivermectin efficacy in nematodes

Guégnard, Fabrice, Aguilaniu, Hugo, Alberich, Mélanie, Partenaires INRAE, Ménez, Cécile, Lespine, Anne, Courtot, Elise, Innovations Thérapeutiques et Résistances (InTheRes), Infectiologie et Santé Publique (UMR ISP), Blanchard, Alexandra

2019

Overview

Resistance to the anthelmintic macrocyclic lactone ivermectin (IVM) has a great impact on the control of parasitic nematodes. The mechanisms by which nematodes adapt to IVM remain to be deciphered. We have identified NHR-8, a nuclear hormone receptor involved in the xenobiotic response in Caenorhabditis elegans, as a new regulator of tolerance to IVM. Loss-of-function nhr-8(ok186) C. elegans mutants subjected to larval development assays and electropharyngeogram measurements, displayed hypersensitivity to IVM, and silencing of nhr-8 in IVM-resistant worms increased IVM efficacy. In addition, compared to wild-type worms, nhr-8 mutants under IVM selection pressure failed to acquire tolerance to the drug. In addition, IVM-hypersensitive nhr-8(ok186) worms displayed low transcript levels of several genes from the xenobiotic detoxification network and a concomitant low Pgp-mediated drug efflux activity. Interestingly, some pgp and cyp genes known to impact IVM tolerance in many nematode species, were down regulated in nhr-8 mutants and inversely upregulated in IVM-resistant worms. Moreover, pgp-6 overexpression in nhr-8(ok186) C. elegans increased tolerance to IVM. Importantly, NHR-8 function was rescued in nhr-8(ok186) C. elegans with the homolog of the parasitic nematode Haemonchus contortus, and silencing of Hco-nhr-8 by RNAi on L2 H. contortus larvae increased IVM susceptibility in both susceptible and resistant H. contortus isolates. Thus, our data show that NHR-8 controls the tolerance and development of resistance to IVM in C. elegans and the molecular basis for this relates to the NHR-8-mediated upregulation of IVM detoxification genes. Since our results show that Hco-nhr-8 functions similarly to Cel-nhr-8, this study helps to better understand mechanisms underlying failure in drug efficacy and open perspectives in finding new compounds with NHR-8 antagonist activity to potentiate IVM efficacy.

• Publisher: CCSD,Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Anthelmintic agents / Anthelmintics / Antiparasitic agents / Biology and Life Sciences / Caenorhabditis elegans / Caenorhabditis elegans - drug effects / Caenorhabditis elegans - metabolism / Caenorhabditis elegans Proteins - drug effects / Caenorhabditis elegans Proteins - metabolism / Caenorhabditis elegans Proteins - physiology / Caprolactone / Cytochrome / Cytochrome P-450 / Detoxification / Dosage and administration / Drug efficacy / Drug Resistance / Drug resistance in microorganisms / Effectiveness / Efflux / Gene expression / Gene Expression Regulation - drug effects / Genes / Glycoproteins / Haemonchus / Homology / Hormones / Hypersensitivity / Ivermectin / Ivermectin - metabolism / Ivermectin - pharmacology / Larva / Larvae / Larval development / Life Sciences / Ligands / Mammals / Medicine and Health Sciences / Metabolism / Methods / Microbial drug resistance / Microbiology and Parasitology / Mutants / Nematoda / Nematode Infections - virology / Nematodes / Nuclear receptors / Parasites / People and Places / Pest resistance / Public health / Receptors, Cytoplasmic and Nuclear - drug effects / Receptors, Cytoplasmic and Nuclear - metabolism / Receptors, Cytoplasmic and Nuclear - physiology / Research and Analysis Methods / RNA interference / RNA-mediated interference / Roundworms / Transcription factors / Transcription Factors - drug effects / Worms / Zinc Finger E-box-Binding Homeobox 1 - drug effects
• ISBN: 0004599721, 9780004599724