Trypanosoma cruzi dormancy and its implications for therapeutic treatment

项目摘要/摘要 微生物休眠，定义为代谢活动减少的状态，在细菌系统中被公认为 对环境压力的瞬时抗性机制，包括抗生素治疗。我们最近报道了 克氏锥虫，恰加斯病的病原体，由于长期接触高细胞毒性化合物而抵抗 细胞内无鞭毛体亚群自发进入休眠状态的能力。这是一项新的 对克氏锥虫生物学的理解对目前可用的药物是如何传递的以及新的药物有多大影响 可以鉴定出能够逆转休眠的化合物。在本申请中，我们提出的实验将 确定克氏锥虫在体内、不同寄生虫分离株、不同寄主组织之间休眠的时间框架和限度 关于感染的长期性。休眠的免疫学意义将被调查。 这些寄生虫学和免疫学信息将被整合起来，以提高目前的治疗效果 可获得的药物。使用一种新的高含量成像屏幕，我们将识别阻止或逆转的小分子 休眠和/或驱动休眠和活跃复制的无鞭毛体向类鞭毛体的阶段转换。 这些化合物将作为研究工具来研究与休眠有关的分子途径，并将 作为恰加斯病新的治疗实体的初步研究。我们认为，休眠现象的观察 和它在药物治疗失败中的明确作用的展示是治疗设计和治疗失败的游戏规则的改变者 克氏锥虫的药物发现。这项提案中的工作为恰加斯病的治疗绘制了一条前进的道路，使用新的 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。

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.