A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance

Beesley, Nicola J ORCID: 0000-0003-0557-1833, Cwiklinski, Krystyna ORCID: 0000-0001-5577-2735, Allen, Katherine, Hoyle, Rebecca C, Spithill, Terry W, La Course, E James, Williams, Diana JL ORCID: 0000-0001-8186-7236, Paterson, Steve ORCID: 0000-0002-1307-2981 and Hodgkinson, Jane E ORCID: 0000-0001-9152-8481 (2023) A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance. PLOS Pathogens, 19 (1). e1011081-e1011081.

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Official URL: http://dx.doi.org/10.1371/journal.ppat.1011081

Abstract

<jats:p><jats:italic>Fasciola hepatica</jats:italic> infection is responsible for substantial economic losses in livestock worldwide and poses a threat to human health in endemic areas. The mainstay of control in livestock and the only drug licenced for use in humans is triclabendazole (TCBZ). TCBZ resistance has been reported on every continent and threatens effective control of fasciolosis in many parts of the world. To date, understanding the genetic mechanisms underlying TCBZ resistance has been limited to studies of candidate genes, based on assumptions of their role in drug action. Taking an alternative approach, we combined a genetic cross with whole-genome sequencing to localise a ~3.2Mbp locus within the 1.2Gbp <jats:italic>F</jats:italic>. <jats:italic>hepatica</jats:italic> genome that confers TCBZ resistance. We validated this locus independently using bulk segregant analysis of <jats:italic>F</jats:italic>. <jats:italic>hepatica</jats:italic> populations and showed that it is the target of drug selection in the field. We genotyped individual parasites and tracked segregation and reassortment of SNPs to show that TCBZ resistance exhibits Mendelian inheritance and is conferred by a dominant allele. We defined gene content within this locus to pinpoint genes involved in membrane transport, (e.g. ATP-binding cassette family B, ABCB1), transmembrane signalling and signal transduction (e.g. GTP-Ras-adenylyl cyclase and EGF-like protein), DNA/RNA binding and transcriptional regulation (e.g. SANT/Myb-like DNA-binding domain protein) and drug storage and sequestration (e.g. fatty acid binding protein, FABP) as prime candidates for conferring TCBZ resistance. This study constitutes the first experimental cross and genome-wide approach for any heritable trait in <jats:italic>F</jats:italic>. <jats:italic>hepatica</jats:italic> and is key to understanding the evolution of drug resistance in <jats:italic>Fasciola</jats:italic> spp. to inform deployment of efficacious anthelmintic treatments in the field.</jats:p>

Item Type:	Article
Uncontrolled Keywords:	Animals, Humans, Fasciola hepatica, Fascioliasis, Benzimidazoles, Anthelmintics, Drug Resistance, Triclabendazole
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	27 Jan 2023 11:52
Last Modified:	14 Apr 2023 11:22
DOI:	10.1371/journal.ppat.1011081
Open Access URL:	https://journals.plos.org/plospathogens/article?id...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3167934