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)夺走了2- 每年有300万人。开发更有效的药物和 疫苗得到加强的原因是：出现了耐多药和极端耐药的结核分枝杆菌 第二，艾滋病毒/艾滋病流行与结核病之间致命的协同作用，原因是 持续细菌的重新激活。这一建议试图检验以下假设： MTB抑制感染诱导的巨噬细胞凋亡是细菌感染的主要途径之一 避免宿主？S的先天免疫和获得性免疫反应。此外，它还建议 参与抑制宿主细胞凋亡的分枝杆菌基因的发现将带来新的 解决持续性细菌感染的药物靶点和新的改进减毒疫苗 菌株。目前，分枝杆菌抑制巨噬细胞凋亡的能力已经被联系起来。 由于缺乏明确的细菌突变体，只能根据相关数据对细菌的毒力进行评估。 提案的目标1旨在通过确定以下几项来填补我们知识的空白 利用一种独特的？功能增益？抑制细胞凋亡的重要分枝杆菌基因？遗传 屏幕上。这种方法的成功已经被一种抗细胞凋亡药物的鉴定所证明。 Mtb基因，nuoG，但至少还有另外两个基因有待鉴定。目标2建议 描述nuoG抑制宿主细胞凋亡的分子机制。 最后，在AIM 3中，细菌突变体被用来解决抑制细胞凋亡的重要性 细菌对宿主的逃逸？S先天和后天免疫应答 免疫缺陷小鼠和免疫活性小鼠。此外，已确定的抗凋亡药物 目前使用的结核疫苗株(BCG)中的基因将被缺失，并对 疫苗潜力上的突变将在结核病的小鼠模型中进行测试。总而言之， 成功完成拟议的研究将导致确定新的结核病药物 目标，并可能导致改进的结核病疫苗毒株。

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.