論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm1800 |