RRC ID 59380
著者 Ménez C, Alberich M, Courtot E, Guegnard F, Blanchard A, Aguilaniu H, Lespine A.
タイトル The transcription factor NHR-8: A new target to increase ivermectin efficacy in nematodes.
ジャーナル PLoS Pathog
Abstract 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.
巻・号 15(2)
ページ e1007598
公開日 2019-2-1
DOI 10.1371/journal.ppat.1007598
PII PPATHOGENS-D-18-01212
PMID 30759156
PMC PMC6391013
MeSH Animals Anthelmintics Caenorhabditis elegans / drug effects Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / drug effects* Caenorhabditis elegans Proteins / metabolism* Caenorhabditis elegans Proteins / physiology Drug Resistance Gene Expression Regulation / drug effects Haemonchus Ivermectin / metabolism* Ivermectin / pharmacology Larva Nematode Infections / virology Receptors, Cytoplasmic and Nuclear / drug effects* Receptors, Cytoplasmic and Nuclear / metabolism* Receptors, Cytoplasmic and Nuclear / physiology Transcription Factors / drug effects Zinc Finger E-box-Binding Homeobox 1 / drug effects
IF 6.463
引用数 8
リソース情報
線虫 tm1800