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.

项目总结/摘要 微生物休眠，定义为代谢活性降低的状态，在细菌系统中被公认为是一种代谢活性降低的状态。 对环境胁迫的短暂抗性机制，包括抗生素治疗。我们最近报道 克氏锥虫，南美锥虫病的病原体，抵抗长期暴露于高细胞毒性化合物， 细胞内无鞭毛体亚群自发地呈现休眠状态的能力。这个新 对T. cruzi生物学对目前可用的药物如何递送以及新药物如何递送具有重要意义。 可以鉴定能够逆转休眠的化合物。在本申请中，我们提出的实验将 定义T的时间范围和限制。克氏休眠在体内，在不同的寄生虫分离物，如果不同的宿主组织 以及感染的慢性程度。将研究休眠的免疫学意义 这些寄生虫学和免疫学信息将被整合，以提高目前使用的治疗效果。 可用的药物。使用一种新型的高容量成像屏幕，我们将识别阻止或逆转 休眠和/或驱动休眠和活跃复制的无鞭毛体向锥鞭毛体的阶段转换。 这些化合物将作为研究工具，研究参与休眠的分子途径， 初步研究作为新的治疗实体的恰加斯病。我们相信对休眠现象的观察 于T. cruzi及其在药物治疗失败中的明确作用的证明是治疗设计的游戏规则改变者， T.克鲁兹这项提案中的工作为治疗恰加斯病指明了前进的道路， 增加我们对决定治疗结果的一组复杂的相互作用力量的理解的工具，以及 整合这些信息以更好地使用现有药物并发现新药物。