Choi Young-Jun, Rosa Bruce A, Fernandez-Baca Martha V, Ore Rodrigo A, Martin John, Ortiz Pedro, Hoban Cristian, Cabada Miguel M, Mitreva Makedonka
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Sede Cusco, Instituto de Medicina Tropical "Alexander von Humboldt", Universidad Peruana Cayetano Heredia, Cusco, Peru.
Nat Commun. 2025 Mar 27;16(1):2996. doi: 10.1038/s41467-025-57796-5.
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 (F 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.
三氯苯达唑（TCBZ）是治疗肝片吸虫病的主要药物，肝片吸虫病是一种由肝片吸虫引起的全球食源性人畜共患病。家畜对TCBZ广泛耐药（TCBZ-R）以及耐药人类感染的迅速增加是重大问题。为了解TCBZ-R的遗传基础，我们对来自秘鲁库斯科146个牛肝脏的99个对TCBZ敏感（TCBZ-S）和210个TCBZ-R成虫吸虫的基因组进行了测序。我们鉴定出高分化的基因组区域（F值超过第99.9百分位数的异常值）编码参与表皮生长因子受体-磷脂酰肌醇-3-激酶-哺乳动物雷帕霉素靶蛋白-核糖体蛋白S6激酶（EGFR-PI3K-mTOR-S6K）途径和微管功能的基因。在未进行药物处理和药物处理后的TCBZ-S和-R吸虫之间，观察到微管相关基因的转录表达差异。仅使用30个单核苷酸多态性（SNP），就有可能以≥75%的准确率区分TCBZ-S和-R寄生虫。我们的异常位点与英国先前报道的与TCBZ-R相关的数量性状位点（QTL）不同，这表明抗性等位基因是独立进化的。基于遗传学的有效TCBZ-R监测必须考虑不同地理种群中选择位点的异质性。
