Mechanism of host cell apoptosis inhibition by Mycobacterium tuberculosis

由结核分枝杆菌(Mtb)感染引起的结核病夺走了200万至300万人的生命 每年都有人。耐多药结核分枝杆菌菌株的出现及其致命的协同作用 艾滋病毒/艾滋病流行和因持续细菌重新激活而导致的结核病加强了 开发更有效的药物和疫苗。这项提议试图检验这样一个假设，即 结核分枝杆菌抑制感染诱导的巨噬细胞凋亡的能力是细菌 避免宿主的先天和适应性免疫反应。此外，它还提出，发现 分枝杆菌参与抑制宿主细胞凋亡的基因将导致新的药物靶点的解析 持续的细菌感染和新的改进的减毒疫苗株。目前， 分枝杆菌抑制巨噬细胞凋亡与细菌毒力的关系仅基于 缺乏明确的细菌突变体的相关数据。提案的目标1旨在填补这一空白 在我们的知识中，通过使用一个独特的“收益”来识别对抑制细胞凋亡重要的分枝杆菌基因 到目前为止，已经鉴定出Mtb的一个抗凋亡基因nuoG。目的2 提出表征nuoG能够抑制宿主细胞凋亡的分子机制。 最后，在AIM 3中，细菌突变体被用来解决抑制细胞凋亡对 在免疫缺陷和获得性免疫反应中细菌逃避宿主的先天性和获得性免疫反应 免疫功能正常的小鼠。此外，已确定的抗凋亡基因将在 目前使用的结核疫苗株(BCG)和突变对疫苗潜力的影响将进行测试 在结核病的小鼠模型中。综上所述，成功完成拟议的研究将导致 确定新的结核病药物靶点，并可能导致改进的结核病疫苗株。相关性：一 世界上三分之一的人口感染了结核分枝杆菌，每年有3000万人 人们会生病，200-300万人死于由此导致的疾病--结核病。该提案旨在确定 细菌内的靶标，用于开发更有效的药物和疫苗。

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infections, claims the lives of 2-3 million people annually. The emergence of multi-drug resistant Mtb strains and the deadly synergism between the HIV/AIDS epidemic and TB due to reactivation of persisting bacteria reinforces the importance of the development of more efficient drugs and vaccines.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 mycobacterial genes important for apoptosis inhibition using a unique "gainof- function" genetic screen. To date one anti-apoptotic gene of Mtb, nuoG, has thus been 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. RELEVANCE: One third of the world's population is infected with Mycobacterium tuberculosis (Mtb) and each year 30 million people get sick and 2-3 million people die of the resulting disease, tuberculosis. The proposal aims to identify targets within the bacteria for the development of more efficient drugs and vaccines.