Transcriptomic analyses implicate neuronal plasticity and chloride homeostasis in ivermectin resistance and response to treatment in a parasitic nematode

Laing, R. et al. (2022) Transcriptomic analyses implicate neuronal plasticity and chloride homeostasis in ivermectin resistance and response to treatment in a parasitic nematode. PLoS Pathogens, 18(6), e1010545. (doi: 10.1371/journal.ppat.1010545) (PMID:35696434) (PMCID:PMC9232149)

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Abstract

The antiparasitic drug ivermectin plays an essential role in human and animal health globally. However, ivermectin resistance is widespread in veterinary helminths and there are growing concerns of sub-optimal responses to treatment in related helminths of humans. Despite decades of research, the genetic mechanisms underlying ivermectin resistance are poorly understood in parasitic helminths. This reflects significant uncertainty regarding the mode of action of ivermectin in parasitic helminths, and the genetic complexity of these organisms; parasitic helminths have large, rapidly evolving genomes and differences in evolutionary history and genetic background can confound comparisons between resistant and susceptible populations. We undertook a controlled genetic cross of a multi-drug resistant and a susceptible reference isolate of Haemonchus contortus, an economically important gastrointestinal nematode of sheep, and ivermectin-selected the F2 population for comparison with an untreated F2 control. RNA-seq analyses of male and female adults of all populations identified high transcriptomic differentiation between parental isolates, which was significantly reduced in the F2, allowing differences associated specifically with ivermectin resistance to be identified. In all resistant populations, there was constitutive upregulation of a single gene, HCON_00155390:cky-1, a putative pharyngeal-expressed transcription factor, in a narrow locus on chromosome V previously shown to be under ivermectin selection. In addition, we detected sex-specific differences in gene expression between resistant and susceptible populations, including constitutive upregulation of a P-glycoprotein, HCON_00162780:pgp-11, in resistant males only. After ivermectin selection, we identified differential expression of genes with roles in neuronal function and chloride homeostasis, which is consistent with an adaptive response to ivermectin-induced hyperpolarisation of neuromuscular cells. Overall, we show the utility of a genetic cross to identify differences in gene expression that are specific to ivermectin selection and provide a framework to better understand ivermectin resistance and response to treatment in parasitic helminths.

Item Type:Articles
Additional Information:Funding: This work was funded by a Biotechnology and Biological Sciences Research Council (BBSRC) strategic Lola [BB/M003949] (RL, DJB, NS, JAC, CB, ED), Scottish Government’s Rural and Environment Science and Analytical Services (RESAS) Division (DJB) and by the Wellcome Trust [206194]. RL is supported by a Wellcome Clinical Research Career Development Fellowship [216614/ Z/19/Z], SRD is supported by a UKRI Future Leaders Fellowship [MR/T020733/1].
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Devaney, Professor Eileen and Tait, Professor Andy and Laing, Dr Roz and Maitland, Ms Kirsty and McIntyre, Dr Jennifer and Britton, Professor Collette
Authors: Laing, R., Doyle, S. R., McIntyre, J., Maitland, K., Morrison, A., Bartley, D. J., Kaplan, R., Chaudhry, U., Sargison, N., Tait, A., Cotton, J. A., Britton, C., and Devaney, E.
College/School:College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Published Online:13 June 2022
Copyright Holders:Copyright: © 2022 Laing et al
First Published:First published in PLoS Pathogens 18(6): e1010545
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190824The BUG consortium Building Upon the Genome: using H. contortus genomic resources to develop novel interventions to control endemic GI parasitesEileen DevaneyBiotechnology and Biological Sciences Research Council (BBSRC)BB/M003949/1Institute of Biodiversity, Animal Health and Comparative Medicine