Tuberculosis Pathogenesis and Drug Response

描述（由申请人提供）：结核病的定义特征是长时间的临床潜伏期，在此期间病原体结核分枝杆菌（Mtb）生长缓慢（如果有的话）。很难夸大这种静止行为的重要性，因为它可能是感染的慢性性质和抗生素相对无效的基础。 尽管越来越多的人认识到静止是一种相对常见的微生物对压力的反应，但这些缓慢复制或非复制细胞的生理状态仍然是个谜。 为了研究向静止的过渡，我们确定了在应激诱导的停滞期间Mtb生长停滞和长期存活所需的基因，以及伴随这种过渡的代谢改变。基于这些互补的研究，我们提出了一个调节级联，感觉宿主衍生的压力，减缓细菌生长，并重塑长期停滞的代谢。 在这个项目中，我们将结合联合收割机高通量遗传和生化方法来确定这种调节途径的结构，并确定其在促进细菌持久性和确定体内药物疗效的最终作用。然后，我们将描述适应静止所需的代谢变化，并确定其中哪些是停滞期生存所必需的。我们的目标是设计新的策略，通过识别和表征维持静止状态所需的细胞通路来加速结核病治疗。

DESCRIPTION (provided by applicant): The defining feature of tuberculosis is the long period of clinical latency during which the causative agent, Mycobacterium tuberculosis (Mtb), grows slowly if at all. It is difficult to overstate the importance of this quiescent behavior, as it likly underlies both the chronic nature of the infection and the relative ineffectiveness of antibiotics. Despite the growing recognition that quiescence is a relatively common microbial response to stress, the physiological state of these slowly- or non-replicating cells has remained enigmatic. To investigate the transition to quiescence, we identified both the genes required for the growth arrest and long-term survival of Mtb during stress-induced stasis, and the metabolic alterations that accompany this transition. Based on these complementary studies, we propose a regulatory cascade that senses host-derived stress, slows bacterial growth, and remodels metabolism for long-term stasis. In this project we will combine high-throughput genetic and biochemical methods to define the structure of this regulatory pathway and determine its ultimate role in promoting bacterial persistence and determining drug efficacy in vivo. We will then characterize the metabolic alterations that are required for the adaptation to quiescence and determine which of these are necessary for survival during stasis. Our goal is to devise new strategies to accelerate tuberculosis therapy through the identification and characterization of cellular pathways that are required for maintaining the quiescent state.