Increased expression of a microRNA correlates with anthelmintic resistance in parasitic nematodes

Gillan, V. et al. (2017) Increased expression of a microRNA correlates with anthelmintic resistance in parasitic nematodes. Frontiers in Cellular and Infection Microbiology, 7, 452. (doi:10.3389/fcimb.2017.00452) (PMID:29209592) (PMCID:PMC5701612)

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Abstract

Resistance to anthelmintic drugs is a major problem in the global fight against parasitic nematodes infecting humans and animals. While previous studies have identified mutations in drug target genes in resistant parasites, changes in the expression levels of both targets and transporters have also been reported. The mechanisms underlying these changes in gene expression are unresolved. Here, we take a novel approach to this problem by investigating the role of small regulatory RNAs in drug resistant strains of the important parasite Haemonchus contortus. microRNAs (miRNAs) are small (22 nt) non-coding RNAs that regulate gene expression by binding predominantly to the 3′ UTR of mRNAs. Changes in miRNA expression have been implicated in drug resistance in a variety of tumor cells. In this study, we focused on two geographically distinct ivermectin resistant strains of H. contortus and two lines generated by multiple rounds of backcrossing between susceptible and resistant parents, with ivermectin selection. All four resistant strains showed significantly increased expression of a single miRNA, hco-miR-9551, compared to the susceptible strain. This same miRNA is also upregulated in a multi-drug-resistant strain of the related nematode Teladorsagia circumcincta. hco-miR-9551 is enriched in female worms, is likely to be located on the X chromosome and is restricted to clade V parasitic nematodes. Genes containing predicted binding sites for hco-miR-9551 were identified computationally and refined based on differential expression in a transcriptomic dataset prepared from the same drug resistant and susceptible strains. This analysis identified three putative target mRNAs, one of which, a CHAC domain containing protein, is located in a region of the H. contortus genome introgressed from the resistant parent. hco-miR-9551 was shown to interact with the 3′ UTR of this gene by dual luciferase assay. This study is the first to suggest a role for miRNAs and the genes they regulate in drug resistant parasitic nematodes. miR-9551 also has potential as a biomarker of resistance in different nematode species.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Devaney, Professor Eileen and Britton, Dr Collette and Skuce, Dr John and Laing, Dr Roz and Gilleard, Professor John and Gillan, Dr Victoria and Winter, Dr Alan and Maitland, Ms Kirsty
Authors: Gillan, V., Maitland, K., Laing, R., Gu, H., Marks, N. D., Winter, A. D., Bartley, D., Morrison, A., Skuce, P. J., Rezansoff, A. M., Gilleard, J. S., Martinelli, A., Britton, C., and Devaney, E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Frontiers in Cellular and Infection Microbiology
Publisher:Frontiers Research Foundation
ISSN:2235-2988
ISSN (Online):2235-2988
Copyright Holders:Copyright © 2017 Gillan, Maitland, Laing, Gu, Marks, Winter, Bartley, Morrison, Skuce, Rezansoff, Gilleard, Martinelli, Britton and Devaney
First Published:First published in Frontiers in Cellular and Infection Microbiology 7:452
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
553351microRNAs and drug resistance in parasitic nematodesEileen DevaneyWellcome Trust (WELLCOTR)094751/Z/10/ZIII - PARASITOLOGY