Tuberculosis Pathogenesis and Drug Response

描述(由申请人提供)：结核病的定义特征是临床潜伏期较长，在此期间，致病菌结核分枝杆菌(Mtb)生长缓慢(如果有的话)。很难夸大这种静止行为的重要性，因为它很可能同时强调了感染的慢性性质和抗生素的相对无效。 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，但这些缓慢或不复制的细胞的生理状态仍然是个谜。为了研究到静止的转变，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，以及伴随着这一转变的代谢变化。基于这些互补性研究，我们提出了一种调节级联反应，可感知宿主来源的压力，减缓细菌生长，并重塑长期停滞的新陈代谢。在这个项目中，我们将结合高通量的遗传和生化方法来定义这一调控途径的结构，并确定其在促进细菌持久性和决定体内药物疗效方面的最终作用。然后，我们将描述适应静止所需的代谢变化，并确定其中哪些是在停滞期间生存所必需的。我们的目标是制定新的策略，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的治疗。

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.