Markers of Triclabendazole Resistant Fascioliasis in the Highlands of Peru

秘鲁高地抗三氯苯达唑片形吸虫病的标志物

• 批准号: 10447025
• 负责人: MIGUEL MAURICIO CABADA
• 金额: $ 48.36万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447025
• 关键词: Address; Adolescent; Adult; Affect; Anemia; Animals; Area; Biological; Biological Process; Body Weight decreased; Bolivia; California; Candidate Disease Gene; Cattle; Child; Clinical; Communities; Complex; Country; Developed Countries; Developing Countries; Development; Diagnosis; Dose; Drug resistance; Early Diagnosis; Early identification; Evaluation; Exposure to; Failure; Fasciola; Fasciola hepatica; Fascioliasis; Florida; Frequencies; Genes; Genetic; Genetic Markers; Genetic Transcription; Genetic Variation; Genome; Genotype; Goals; Grant; Hawaii; Health; Hepatica; Human; Impaired cognition; Income; Individual; Industry; Infection; Intervention; Knowledge; Livestock; Maps; Metabolism; Metadata; Migrant; Modeling; Monitor; Mutation; Nature; Outcome; Parasite resistance; Parasites; Parasitic infection; Pathway interactions; Pattern; Persons; Peru; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Production; Puerto Rico; Refugees; Reporting; Resistance; Sampling; Sheep; Specimen; System; Time; Transcription Alteration; Trematoda; Trematode Infections; Ursidae Family; Variant; World Health Organization; Zoonoses; biomarker identification; biomarker validation; clinical predictors; clinically relevant; cohort; diagnostic biomarker; diagnostic tool; food security; foodborne; genetic architecture; genetic variant; genome analysis; genome wide association study; genome-wide; innovation; long-term sequelae; neglect; neglected tropical diseases; predictive marker; prevent; resistance mechanism; response; targeted sequencing; tool; transcriptome; uptake

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.

项目概要/摘要 片形吸虫病是一种全球食源性吸虫感染，世界卫生组织将其列为重要的被忽视的热带病 由于该疾病对世界各地的人类和牲畜种群造成严重影响。三氯苯达唑是唯一 建议使用药物进行治疗，但耐药性在牲畜中普遍存在，并且是一个新出现的问题 在受感染的人中。三氯苯达唑耐药机制尚不清楚，也没有可靠的证据 预测感染对象易感性表型的标记。针对性评价具体 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。目前的提案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，发现与三氯苯达唑耐药性相关 感染动物，包括敏感菌株和三氯苯达唑耐药菌株。与抗性相关的位点将 使用感染人类的​​寄生虫进行验证，因为我们假设，由于 F. 在肝脏中，导致动物和人类宿主产生耐药性的变异是保守的。最后，当前 拨款将评估暴露于不同剂量的片形吸虫不同阶段的转录反应 三氯苯达唑揭示诱导三氯苯达唑耐药的机制。这是一个全面的 建议完成后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组可靠的遗传标记来区分 抗性和易感片形吸虫寄生虫之间。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，指导感染受试者的治疗，并提供 管理和控制策略的指导。识别和恢复改变的途径也可能有所帮助 克服阻力，使 TCBZ 再次发挥作用。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。

项目成果

The Differences in the Susceptibility Patterns to Triclabendazole Sulfoxide in Field Isolates of Fasciola hepatica Are Associated with Geographic, Seasonal, and Morphometric Variations.

肝片形吸虫现场分离株对三氯苯达唑亚砜敏感性模式的差异与地理、季节和形态变化有关。

• 发表时间: 2022-05-28
• 作者: Fernandez;Hoban, Cristian;Ore, Rodrigo A;Ortiz, Pedro;Choi, Young;Murga;Mitreva, Makedonka;Cabada, Miguel M
• 通讯作者: Cabada, Miguel M