Genomic landscape of drug response reveals mediators of anthelmintic resistance

Stephen R. Doyle; Roz Laing; David Bartley; Alison Morrison; Nancy Holroyd; Kirsty Maitland; Alistair Antonopoulos; Umer Chaudhry; Ilona Flis; Sue Howell; Jennifer McIntyre; John S. Gilleard; Andy Tait; Barbara Mable; Ray Kaplan; Neil Sargison; Collette Britton; Matthew Berriman; Eileen Devaney; James A. Cotton

doi:10.1016/j.celrep.2022.111522

Genomic landscape of drug response reveals mediators of anthelmintic resistance

Stephen R. Doyle, Roz Laing, David Bartley, Alison Morrison, Nancy Holroyd, Kirsty Maitland, Alistair Antonopoulos, Umer Chaudhry, Ilona Flis, Sue Howell, Jennifer McIntyre, John S. Gilleard, Andy Tait, Barbara Mable, Ray Kaplan, Neil Sargison, Collette Britton, Matthew Berriman, Eileen Devaney, James A. Cotton

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

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.

Original language	English
Article number	111522
Journal	Cell Reports
Volume	41
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2022.111522
Publication status	Published - 18 Oct 2022
Externally published	Yes

Keywords

anthelmintic resistance
benzimidazole
cky-1
CP: Microbiology
CP: Molecular biology
forward genetics
genetic cross
genome-wide association
Haemonchus contortus
helminth
ivermectin
levamisole

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10.1016/j.celrep.2022.111522Licence: CC BY

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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., & Cotton, J. A. (2022). Genomic landscape of drug response reveals mediators of anthelmintic resistance. Cell Reports, 41(3), Article 111522. https://doi.org/10.1016/j.celrep.2022.111522

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title = "Genomic landscape of drug response reveals mediators of anthelmintic resistance",

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.",

keywords = "anthelmintic resistance, benzimidazole, cky-1, CP: Microbiology, CP: Molecular biology, forward genetics, genetic cross, genome-wide association, Haemonchus contortus, helminth, ivermectin, levamisole",

author = "Doyle, \{Stephen R.\} and Roz Laing and David Bartley and Alison Morrison and Nancy Holroyd and Kirsty Maitland and Alistair Antonopoulos and Umer Chaudhry and Ilona Flis and Sue Howell and Jennifer McIntyre and Gilleard, \{John S.\} and Andy Tait and Barbara Mable and Ray Kaplan and Neil Sargison and Collette Britton and Matthew Berriman and Eileen Devaney and Cotton, \{James A.\}",

year = "2022",

month = oct,

day = "18",

doi = "10.1016/j.celrep.2022.111522",

language = "English",

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journal = "Cell Reports",

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Doyle, SR, Laing, R, Bartley, D, Morrison, A, Holroyd, N, Maitland, K, Antonopoulos, A, Chaudhry, U, Flis, I, Howell, S, McIntyre, J, Gilleard, JS, Tait, A, Mable, B, Kaplan, R, Sargison, N, Britton, C, Berriman, M, Devaney, E & Cotton, JA 2022, 'Genomic landscape of drug response reveals mediators of anthelmintic resistance', Cell Reports, vol. 41, no. 3, 111522. https://doi.org/10.1016/j.celrep.2022.111522

TY - JOUR

T1 - Genomic landscape of drug response reveals mediators of anthelmintic resistance

AU - Doyle, Stephen R.

AU - Laing, Roz

AU - Bartley, David

AU - Morrison, Alison

AU - Holroyd, Nancy

AU - Maitland, Kirsty

AU - Antonopoulos, Alistair

AU - Chaudhry, Umer

AU - Flis, Ilona

AU - Howell, Sue

AU - McIntyre, Jennifer

AU - Gilleard, John S.

AU - Tait, Andy

AU - Mable, Barbara

AU - Kaplan, Ray

AU - Sargison, Neil

AU - Britton, Collette

AU - Berriman, Matthew

AU - Devaney, Eileen

AU - Cotton, James A.

PY - 2022/10/18

Y1 - 2022/10/18

N2 - 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.

AB - 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.

KW - anthelmintic resistance

KW - benzimidazole

KW - cky-1

KW - CP: Microbiology

KW - CP: Molecular biology

KW - forward genetics

KW - genetic cross

KW - genome-wide association

KW - Haemonchus contortus

KW - helminth

KW - ivermectin

KW - levamisole

U2 - 10.1016/j.celrep.2022.111522

DO - 10.1016/j.celrep.2022.111522

M3 - Article

SN - 2639-1856

VL - 41

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 111522

ER -

Genomic landscape of drug response reveals mediators of anthelmintic resistance

Abstract

Keywords

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