LIFE CYCLE STAGES AND PATHOGENICITY OF M TUBERCULOSIS

结核分枝杆菌在过去十年中重新出现， 城市中心和免疫功能低下人群的健康风险增加 个体病原体的成功在很大程度上是由于其 感染并在宿主的吞噬细胞中存活的能力。古典 结核病是一种潜伏感染的重新激活， 宿主和病原体之间的联系明显地转向了 细菌 结核分枝杆菌与宿主之间的这种微妙的相互作用， 人们对此知之甚少，但它是控制结核病的关键。的 细菌的生物学及其细胞内环境位于 从休眠状态到爆发性感染的转变中心。 虽然分枝杆菌没有表现出明确的形态分化 在它的生命周期中，我们发现它的环境可以显著地 改变其蛋白质合成的模式，揭示了一系列独特的 细胞内"停滞"和"生长"多肽。 在本提案中，我们描述了一种综合方法，使我们能够 确定M. 结核病和表征蛋白质合成谱的 细胞内"停滞"和"复制"的生命周期阶段的 细菌。 这些信息将被应用于理解 在鼠肺模型中再活化结核的生物学。的 感染灶的发展将通过实验来控制 通过使用"敲除"小鼠和调节细胞免疫， 反应

Mycobacterium tuberculosis has re-emerged over the last decade as an increasing health risk in inner cities and in immunocompromised individuals. The success of the pathogen is due in large part to its ability to infect and persist within the phagocytes of its host. Classical tuberculosis is the reactivation of a latent infection where the balance between the host and pathogen has apparently shifted in favor of the bacteria. This delicate interplay between Mycobacterium tuberculosis and its host is poorly understood yet it holds the key to the control of tuberculosis. The biology of the bacterium and its intracellular environment lie at the center of the transition from a dormant state to a fulminating infection. Although Mycobacterium does not show clear morphological differentiation during its life cycle we have found that its environment can markedly alter its pattern of protein synthesis, revealing distinctive sets of intracellular "stasis" and "growth" polypeptides. In this proposal we describe an integrated approach that will enable us to define the properties of the intramacrophage vacuole inhabited by M. tuberculosis and characterize the protein synthesis profiles of the intracellular "stasis" and "replicative" life cycle stages of the bacterium. This information will then be applied to understanding the biology of reactivation tuberculosis in a murine lung model. The development of the infection foci will be experimentally manipulated through the use of "knockout" mice and modulation of the cellular immune response.