Genomic landscape of drug response reveals mediators of anthelmintic resistance

Doyle, S. R. et al. (2022) Genomic landscape of drug response reveals mediators of anthelmintic resistance. Cell Reports, 41(3), 111522. (doi: 10.1016/j.celrep.2022.111522) (PMID:36261007) (PMCID:PMC9597552)

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Like other pathogens, parasitic helminths can rapidly evolve resistance to drug treatment. Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to tracking its spread and improving the efficacy and sustainability of parasite control. Here, we use an in vivo genetic cross between drug-susceptible and multi-drug-resistant strains of Haemonchus contortus in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies new alleles for resistance to benzimidazoles and levamisole and implicates the transcription factor cky-1 in ivermectin resistance. This gene is within a locus under selection in ivermectin-resistant populations worldwide; expression analyses and functional validation using knockdown experiments support that cky-1 is associated with ivermectin survival. Our work demonstrates the feasibility of high-resolution forward genetics in a parasitic nematode and identifies variants for the development of molecular diagnostics to combat drug resistance in the field.

Item Type:Articles
Keywords:Levamisole, levamisole, genomics, cky-1, Haemonchus contortus, anthelmintics - pharmacology - therapeutic use, benzimidazoles, genome-wide association, forward genetics, drug resistance - genetics, anthelmintic resistance, genetic cross, helminth, ivermectin, CP: molecular biology, Ivermectin - pharmacology, benzimidazole, transcription factors, CP: microbiology.
Glasgow Author(s) Enlighten ID:Cotton, Professor James and Devaney, Professor Eileen and Mable, Professor Barbara and McIntyre, Dr Jennifer and Britton, Professor Collette and Tait, Professor Andy and Flis, Ms Ilona and Laing, Dr Roz and Antonopoulos, Mr Alistair and Maitland, Ms Kirsty
Authors: Doyle, S. R., Laing, R., Bartley, D., Morrison, A., Holroyd, N., Maitland, K., Antonopoulos, A., Chaudhry, U., Flis, I., Howell, S., McIntyre, J., Gilleard, J. S., Tait, A., Mable, B., Kaplan, R., Sargison, N., Britton, C., Berriman, M., Devaney, E., and Cotton, J. A.
College/School:College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN (Online):2211-1247
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cell Reports 41(3):111522
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
301517Maintaining a unique parasite life cycle and development of post-genomic resourcesEileen DevaneyWellcome Trust (WELLCOTR)208390/Z/17/ZInstitute of Biodiversity, Animal Health and Comparative Medicine
306505Hitting a moving target: genomic and metabolic approaches to improve anthelmintic use in evolving helminth populationsRosalind LaingWellcome Trust (WELLCOTR)216614/Z/19/ZMVLS - Polyomics Facility