Trypanosoma cruzi dormancy and its implications for therapeutic treatment

克氏锥虫休眠及其对治疗的影响

• 批准号: 10573204
• 负责人: Rick L Tarleton
• 金额: $ 47.7万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573204
• 关键词: Acute; Adverse effects; Animals; Antibiotic Therapy; Antiparasitic Agents; Benznidazole; Biology; Chagas Disease; Characteristics; Chronic; Combination Drug Therapy; Complex; Detection; Development; Drug resistance; Drug usage; Exclusion; Exposure to; Frequencies; Goals; Heart Diseases; Human; Image; Immune; Immune response; Immune system; Immunologics; Immunotherapy; In Vitro; Individual; Infection; Insecta; Investigation; Life; Light; Link; Location; Metabolic; Microscopy; Molecular; Monitor; Organ; Outcome; Parasites; Parasitology; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Process; Property; Regimen; Reporting; Research; Resistance; Risk; Role; System; Therapeutic; Tissues; Treatment Efficacy; Treatment Failure; Treatment Protocols; Treatment outcome; Trypanocidal Agents; Trypanosoma cruzi; Work; acute infection; chronic infection; cytotoxic; design; drug discovery; drug efficacy; effective therapy; environmental stressor; experimental study; improved; in vivo; microbial; novel; novel therapeutic intervention; novel therapeutics; prevent; small molecule; therapeutic candidate; therapy design; tool; transmission process

Project Summary/Abstract Microbial dormancy, defined as a state of reduced metabolic activity, is well recognized in bacterial systems as a mechanism of transient resistance to environmental stresses, including antibiotic treatment. We have recently reported that Trypanosoma cruzi, the agent of Chagas disease, resists long-term exposure to highly cytotoxic compounds due to the ability of a subpopulation of intracelllular amastigotes to spontaneously assume a dormant state. This new understanding of T. cruzi biology has implications for how currently available drugs are delivered and how new compounds capable of reversing dormancy, may be identified. In this application, we propose experiments that will define the timeframe and limits of T. cruzi dormancy in vivo, among different parasite isolates, if different host tissues and with respect to the chronicity of the infections. The immunological implications of dormancy will be investigated and this parasitological and immunological information will be integrated to enhance treatment efficacy using currently available drugs. Using a novel high content imaging screen, we will identify small molecules that prevent or reverse dormancy and/or drive the stage conversion of both dormant and actively replicating amastigotes into trypomastigotes. These compounds will serve as research tools to investigate the molecular pathways involved in dormancy and will be preliminarily investigated as new therapeutic entities for Chagas disease. We believe that the observation of dormancy in T. cruzi and the demonstration of its clear role in drug treatment failure is a game changer for treatment design and drug discovery in T. cruzi. The work in this proposal charts a way forward for therapy for Chagas disease, using new tools to increase our understanding of the complex set of interacting forces that determine treatment outcomes, and integrating this information to better use current drugs and discover of new ones.

项目摘要/摘要 微生物休眠，被定义为降低代谢活性的状态，在细菌系统中被广泛认可为 瞬时抵抗环境应力的机制，包括抗生素治疗。我们最近报告了 Cruzi锥虫是Chagas疾病的药物，它抵抗了由于高度细胞毒性化合物的长期暴露 细胞内膜片的亚群自发假定状态的能力。这个新 对T. Cruzi生物学的了解对当前可用药物的交付以及如何新 可以鉴定出能够逆转休眠的化合物。在此应用程序中，我们提出的实验将 在不同的寄生虫分离株之间，定义体内t. cruzi休眠的时间范围和限制，如果不同的宿主组织 以及感染的慢性性。休眠的免疫学意义将被研究 这种寄生学和免疫学信息将集成以增强治疗疗效 可用的药物。使用新颖的高内容成像屏幕，我们将确定预防或反向的小分子 休眠和/或驱动休眠和主动将杂物的阶段转化为锥虫。 这些化合物将作为研究休眠所涉及的分子途径的研究工具，将是 初步研究是chagas病的新治疗实体。我们认为观察休眠 在克鲁齐（T. T. Cruzi的药物发现。该提案中的工作图表了使用新的 提高我们对确定治疗结果的复杂相互作用的理解的工具，并 整合此信息以更好地使用当前药物并发现新的药物。