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.
Highlights
Helminth infections affect nearly three billion people worldwide and cause the highest economic losses in livestock due to lower productivity
Since Nuclear Hormone Receptors (NHRs)-8 was discovered to determine IVM tolerance, we explored its role in the transcriptional regulation of the drug detoxification network and identified some genes that were regulated by NHR-8, that are important for IVM tolerance
In order to identify transcriptional regulators that could be involved in susceptibility to IVM in C. elegans, three strains (AE501 nhr-8(ok186), AA107 nhr-48(ok178) and DR20 daf-12 (m20)), each lacking function of individual NHRs, NHR-8, NHR-48 and DAF-12 respectively, were subjected to a larval development assay in the presence of the drug
Summary
Helminth infections affect nearly three billion people worldwide and cause the highest economic losses in livestock due to lower productivity. Ivermectin (IVM) is an antiparasitic compound, belonging to the macrocyclic lactone (ML) family, used worldwide for the control of endo- and ecto-parasites in veterinary and human medicine [1]. IVM was first approved for use in the veterinary field and remains the only ML available for mass chemotherapy in human onchocerciasis and strongyloidiasis. IVM resistance is rampant in parasites of ruminants and horses [2,3], and IVM loss-of-efficacy is observed in dog [4] and human parasites [5]. Because of the increasing limitations of existing products, there is an urgent need to discover new agents active against resistant parasitic nematodes and to identify additional biological targets. Innovation in anthelmintic discovery will depend on advancing knowledge on the mechanisms involved in the development of drug resistance in nematodes
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