LIFE CYCLE STAGES AND PATHOGENICITY OF M TUBERCULOSIS

在过去的十年里，结核分枝杆菌作为一种 市中心和免疫系统受损人群的健康风险增加 个人。病原体的成功在很大程度上要归功于它的 在宿主的吞噬细胞内感染并持续存在的能力。古典主义 结核病是潜伏感染的重新激活，在那里平衡 宿主和病原体之间的关系显然转向了有利于 细菌。 结核分枝杆菌与其宿主之间的这种微妙的相互作用 人们对此知之甚少，但它掌握着控制结核病的关键。这个 细菌的生物学和它的胞内环境在于 从休眠状态过渡到暴发性感染的中心。 虽然分枝杆菌的形态分化不明显 在它的生命周期中，我们发现它的环境可以显著地 改变它的蛋白质合成模式，揭示出独特的 细胞内的“停滞”和“生长”多肽。 在这份提案中，我们描述了一种综合方法，它将使我们能够 定义巨噬细胞内M。 结核分枝杆菌的蛋白质合成图谱 细胞内“停滞”和“复制”的生命周期阶段 细菌。然后，这些信息将被用于理解 在小鼠肺模型中重新激活结核的生物学。这个 将对感染源的发展进行实验操作 通过使用“基因敲除”小鼠和调节细胞免疫 回应。

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.