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)

Abstract

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.
• Status: Published
• Refereed: Yes
• 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: 2211-1247
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190824		The BUG consortium Building Upon the Genome: using H. contortus genomic resources to develop novel interventions to control endemic GI parasites	Eileen Devaney	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/M003949/1	Institute of Biodiversity, Animal Health and Comparative Medicine
301517		Maintaining a unique parasite life cycle and development of post-genomic resources	Eileen Devaney	Wellcome Trust (WELLCOTR)	208390/Z/17/Z	Institute of Biodiversity, Animal Health and Comparative Medicine
306505		Hitting a moving target: genomic and metabolic approaches to improve anthelmintic use in evolving helminth populations	Rosalind Laing	Wellcome Trust (WELLCOTR)	216614/Z/19/Z	MVLS - Polyomics Facility