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

基本信息

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
项目类别：
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

项目摘要

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。