A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance.
Fasciola hepatica 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 eve...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1011081 |
| _version_ | 1797903306650025984 |
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| author | Nicola J Beesley Krystyna Cwiklinski Katherine Allen Rebecca C Hoyle Terry W Spithill E James La Course Diana J L Williams Steve Paterson Jane E Hodgkinson |
| author_facet | Nicola J Beesley Krystyna Cwiklinski Katherine Allen Rebecca C Hoyle Terry W Spithill E James La Course Diana J L Williams Steve Paterson Jane E Hodgkinson |
| author_sort | Nicola J Beesley |
| collection | DOAJ |
| description | Fasciola hepatica 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 F. hepatica genome that confers TCBZ resistance. We validated this locus independently using bulk segregant analysis of F. hepatica 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 F. hepatica and is key to understanding the evolution of drug resistance in Fasciola spp. to inform deployment of efficacious anthelmintic treatments in the field. |
| first_indexed | 2024-04-10T09:30:48Z |
| format | Article |
| id | doaj.art-47274f3eaf804c1e88d60db0e5999538 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-10T09:30:48Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-47274f3eaf804c1e88d60db0e59995382023-02-19T05:31:11ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-01-01191e101108110.1371/journal.ppat.1011081A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance.Nicola J BeesleyKrystyna CwiklinskiKatherine AllenRebecca C HoyleTerry W SpithillE James La CourseDiana J L WilliamsSteve PatersonJane E HodgkinsonFasciola hepatica 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 F. hepatica genome that confers TCBZ resistance. We validated this locus independently using bulk segregant analysis of F. hepatica 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 F. hepatica and is key to understanding the evolution of drug resistance in Fasciola spp. to inform deployment of efficacious anthelmintic treatments in the field.https://doi.org/10.1371/journal.ppat.1011081 |
| spellingShingle | Nicola J Beesley Krystyna Cwiklinski Katherine Allen Rebecca C Hoyle Terry W Spithill E James La Course Diana J L Williams Steve Paterson Jane E Hodgkinson A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance. PLoS Pathogens |
| title | A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance. |
| title_full | A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance. |
| title_fullStr | A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance. |
| title_full_unstemmed | A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance. |
| title_short | A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance. |
| title_sort | major locus confers triclabendazole resistance in fasciola hepatica and shows dominant inheritance |
| url | https://doi.org/10.1371/journal.ppat.1011081 |
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