Mechanism of host cell apoptosis inhibition by Mycobacterium tuberculosis

由结核分枝杆菌（Mtb）感染引起的结核病（TB）夺去了2- 每年300万人。开发更有效的药物的重要性， 多重耐药和极端耐药结核分枝杆菌的出现 其次，艾滋病毒/艾滋病流行病和结核病之间的致命协同作用， 这一提议旨在检验以下假设： MTB抑制感染诱导的巨噬细胞凋亡是该菌的主要途径 避开主人？的先天性和适应性免疫反应。此外，它还建议， 发现参与抑制宿主细胞凋亡的分枝杆菌基因将导致新的 用于解决持续性细菌感染的药物靶标和新的改进的减毒疫苗 菌株目前，分枝杆菌抑制巨噬细胞凋亡的能力已经与 由于缺乏确定的细菌突变体，细菌毒力仅基于相关数据。 该提案的目的1旨在通过确定几个 分枝杆菌基因重要的细胞凋亡抑制使用一个独特的？功能增益遗传 屏幕这种方法的成功已经通过鉴定一种抗凋亡的 Mtb的nuoG基因，但至少还有两个其他基因有待鉴定。AIM 2建议， 表征nuoG能够抑制宿主细胞凋亡的分子机制。 最后，在AIM 3中，细菌突变体用于解决细胞凋亡抑制的重要性 细菌从宿主体内逃逸的先天性和获得性免疫反应， 免疫缺陷和免疫活性小鼠。此外，所鉴定的抗凋亡 目前使用的结核病疫苗株（BCG）中的基因将被删除， 将在结核病小鼠模型中测试突变对疫苗潜力的影响。一切器皿的银子 成功完成拟议的研究将有助于确定新的结核病药物 目标，并可能导致改进的结核病疫苗株。

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infections, claims the lives of 2- 3 million people annually. The importance of the development of more efficient drugs and vaccines is reinforced by: the emergence of multi-drug resistant and extreme-drug resistant Mtb strains and secondly, the deadly synergism between the HIV/AIDS epidemic and TB due to reactivation of persisting bacteria.This proposal seeks to test the hypothesis that the capacity of Mtb to inhibit infection-induced apoptosis of macrophages is a major pathway of the bacteria to avoid the host?s innate and adaptive immune response. Furthermore it proposes that the discovery of mycobacterial genes involved in the inhibition of host cell apoptosis will lead to new drug targets for resolving persistent bacterial infections and to new improved attenuated vaccine strains. Presently, the capacity of mycobacteria to inhibit macrophage apoptosis has been linked to bacterial virulence based only on correlative data due to the lack of defined bacterial mutants. The AIM 1 of the proposal targets to fill that gap in our knowledge by identifying several mycobacterial genes important for apoptosis inhibition using a unique ?gain-of-function? genetic screen. The success of this approach has been proven by the identification of one anti-apoptotic gene of Mtb, nuoG, but at least two additional genes remain to be identified. AIM 2 proposes to characterize the molecular mechanisms by which nuoG is able to suppress host cell apoptosis. Finally, in AIM 3 the bacterial mutants are used to address the importance of apoptosis inhibition for the bacterial escape from the host?s innate and acquired immune response in immunodeficient and immunocompetent mice, respectively. In addition, the identified anti-apoptotic gene will be deleted in the currently used TB vaccine strain (BCG) and the effect of the mutation on the vaccine potential will be tested in the mouse model of TB. Altogether, the successful completion of the proposed studies would lead to the identification of new TB drug targets and may result in an improved TB vaccine strain.