Independent origins and non-parallel selection signatures of triclabendazole resistance in Fasciola hepatica

Young-Jun Choi, Bruce A. Rosa, Martha V. Fernandez-Baca, Rodrigo A. Ore, John Martin, Pedro Ortiz, Cristian Hoban, Miguel M. Cabada () and Makedonka Mitreva ()
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Young-Jun Choi: Washington University School of Medicine
Bruce A. Rosa: Washington University School of Medicine
Martha V. Fernandez-Baca: Universidad Peruana Cayetano Heredia
Rodrigo A. Ore: Universidad Peruana Cayetano Heredia
John Martin: Washington University School of Medicine
Pedro Ortiz: Universidad Nacional de Cajamarca
Cristian Hoban: Universidad Nacional de Cajamarca
Miguel M. Cabada: Universidad Peruana Cayetano Heredia
Makedonka Mitreva: Washington University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Triclabendazole (TCBZ) is the primary treatment for fascioliasis, a global foodborne zoonosis caused by Fasciola hepatica. Widespread resistance to TCBZ (TCBZ-R) in livestock and a rapid rise in resistant human infections are significant concerns. To understand the genetic basis of TCBZ-R, we sequenced the genomes of 99 TCBZ-sensitive (TCBZ-S) and 210 TCBZ-R adult flukes from 146 bovine livers in Cusco, Peru. We identify genomic regions of high differentiation (FST outliers above the 99.9th percentile) that encod genes involved in the EGFR-PI3K-mTOR-S6K pathway and microtubule function. Transcript expression differences are observed in microtubule-related genes between TCBZ-S and -R flukes, both without drug treatment and in response to treatment. Using only 30 SNPs, it is possible to differentiate between TCBZ-S and -R parasites with ≥75% accuracy. Our outlier loci are distinct from the previously reported TCBZ-R-associated QTLs in the UK, suggesting an independent evolution of resistance alleles. Effective genetics-based TCBZ-R surveillance must consider the heterogeneity of loci under selection across diverse geographical populations.

Date: 2025
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DOI: 10.1038/s41467-025-57796-5

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