Markers of Triclabendazole Resistant Fascioliasis in the Highlands of Peru

项目摘要/摘要 肝片吸虫病是一种全球食源性吸虫感染，世卫组织将其列为一种重要的被忽视的热带疾病 由于它对世界各地的人和牲畜种群有很大的影响，因此它是一种疾病。三氯苯达唑是唯一 推荐用于治疗的药物，但耐药性在家畜中普遍存在，是一个新出现的问题 在受感染的人类中。三氯苯达唑的耐药机制尚不清楚，也没有可靠的 预测感染者易感表型的标记物。有针对性地评估特定的 候选基因产生了不一致的结果，可能是由于基因-表型的复杂性 两性关系。目前的提议将使用全基因组关联的方法来识别 通过分析大量片吸虫寄生虫的基因组发现与三氯苯达唑耐药性有关 感染动物，包括敏感和对三氯苯达唑具有抗药性的菌株。与抗性相关的基因座将 使用感染人类的寄生虫进行验证，因为我们假设，由于F. 在动物和人类宿主中导致抗药性的变异是保守的。最后，当前 格兰特将评估不同剂量的片形吸虫对不同阶段的转录反应 三氯苯达唑，以揭示导致三氯苯达唑耐药的机制。这是一个全面的 建议，一旦完成，将提供对生物过程的机械理解， 确定三氯苯达唑耐药表型和一套可靠的区分 在抵抗和敏感的片状吸虫寄生虫之间。从长远来看，这项研究的结果可能会让 创建早期识别TCBZ-R的诊断工具，以指导感染对象的治疗，并提供 管理和控制策略的指导。识别和恢复改变的通路也可能有所帮助 克服阻力，使TCBZ再次有效。此外，我们还将建立一个模型来研究其他 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.