Markers of Triclabendazole Resistant Fascioliasis in the Highlands of Peru

项目概要/摘要 肝片吸虫病是一种全球性食源性吸虫感染，世卫组织将其作为一种重要的被忽视的热带疾病， 由于其对世界各地的人类和牲畜种群的高度影响，三氯苯达唑是唯一 推荐用于治疗的药物，但抗药性在牲畜中广泛存在，是一个新出现的问题 感染的人。三氯苯达唑耐药的机制尚不清楚，也没有可靠的 预测感染受试者中易感性表型的标志物。有针对性地评价具体 候选基因产生了不一致的结果，可能是由于基因型-表型的复杂性 关系。目前的提议将使用全基因组关联方法来识别遗传变异， 通过分析大量片形吸虫寄生虫的基因组， 感染动物，包括敏感和三氯苯达唑耐药分离株。抗性相关基因座将 使用人类感染的寄生虫进行验证，因为我们假设，由于F. 肝细胞癌中，在动物和人类宿主中导致抗性的变体是保守的。最后，当前 格兰特将评估不同阶段的片形吸虫暴露于不同剂量的 三氯苯达唑，以揭示机制，诱导耐药三氯苯达唑。这是一个全面的 建议，完成后将提供一个生物过程的机械理解， 确定三氯苯达唑耐药表型和一组可靠的遗传标记， 抵抗性和敏感性片形吸虫寄生虫之间的区别从长远来看，这项研究的结果可能会使 创建用于早期识别TCBZ-R的诊断工具，以指导感染受试者的治疗，并提供 指导管理和控制策略。识别和恢复改变的途径也可能有助于 克服阻力，使TCBZ再次发挥作用。此外，我们将建立一个模型来研究其他的 具有复杂生命周期的吸虫寄生虫。

PROJECT SUMMARY/ABSTRACT Fascioliasis is a global food-borne trematode infection targeted by WHO as an important neglected tropical disease due to its high impact in human and livestock populations around the world. Triclabendazole is the only drug recommended for treatment, but drug resistance is widespread in livestock and is an emerging problem among infected humans. The mechanisms of triclabendazole resistance are not known and there are no reliable markers that predict the susceptibility phenotype among infected subjects. Targeted evaluation of specific candidate genes has yielded inconsistent results, likely due to the complexity of genotype-phenotype relationships. The current proposal will use a genome-wide association approach to identify genetic variants that are associated with triclabendazole resistance by analyzing the genomes of a large number of Fasciola parasites infecting animals, including susceptible and triclabendazole-resistant isolates. The resistance-associated loci will be validated using human-infecting parasites because we hypothesize that, due to the zoonotic nature of F. hepatica, the variants contributing to resistance in animal and human hosts are conserved. Lastly, the current grant will evaluate the transcriptional response of different stages of Fasciola exposed to various doses of triclabendazole to uncover the mechanisms that induce resistance to triclabendazole. This is a well-rounded proposal that upon completion will provide a mechanistic understanding of the biological processes that determine the triclabendazole resistance phenotype and a set of reliable genetic markers that distinguish between resistant and susceptible Fasciola parasites. In the long term, the results of this study may allow the creation of diagnostic tools for early identification of TCBZ-R, to direct treatment of infected subjects, and provide guidance for stewardship and control strategies. Identifying and restoring altered pathways may also help overcome resistance and make TCBZ effective again. In addition, we will set-up of a model to study other trematode parasites with complex lifecycles.