Genomic landscape of drug response reveals mediators of anthelmintic resistance.
CP: Microbiology
CP: Molecular biology
Haemonchus contortus
anthelmintic resistance
benzimidazole
cky-1
forward genetics
genetic cross
genome-wide association
helminth
ivermectin
levamisole
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
18 10 2022
18 10 2022
Historique:
received:
18
02
2022
revised:
11
07
2022
accepted:
26
09
2022
entrez:
19
10
2022
pubmed:
20
10
2022
medline:
22
10
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36261007
pii: S2211-1247(22)01377-8
doi: 10.1016/j.celrep.2022.111522
pmc: PMC9597552
pii:
doi:
Substances chimiques
Ivermectin
70288-86-7
Levamisole
2880D3468G
Anthelmintics
0
Benzimidazoles
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
111522Subventions
Organisme : Wellcome Trust
ID : 206194
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T020733/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 208390/Z/17/Z
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M003949
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 216614/Z/19/Z
Pays : United Kingdom
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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