Post Translation Regulation in Mycobacteria

分枝杆菌的翻译后调控

• 批准号: 7460732
• 负责人: Luiz Eduardo Bermudez
• 金额: $ 17.93万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460732
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animal Model; Animals; Bacteria; Brucella abortus; Cells; Chronic; Code; Communicable Diseases; Condition; Developed Countries; Developing Countries; Disease; Endopeptidases; Environment; Epithelial; Epithelial Cells; Escherichia coli; Future; Gene Expression; Gene Expression Regulation; Genes; Genus Mycobacterium; HIV-1; Human; Hydrogen Peroxide; In Vitro; Individual; Infection; Intestinal Mucosa; Intestines; Invaded; Ions; Knock-out; Literature; Lung; Mediating; Mucous Membrane; Mus; Mycobacterium avium; Mycobacterium tuberculosis; Numbers; Pathogenicity Island; Patients; Peptide Hydrolases; Polysaccharides; Population; Post-Translational Regulation; Predisposition; Production; Proteins; Proteolysis; Pulmonary Emphysema; Regulation; Role; Salmonella; Salmonella typhimurium; Signal Transduction; Staging; Stress; Transcription Coactivator; Translations; Tuberculosis; Virulence; Work; attenuation; bactericide; biological adaptation to stress; colanic acid; endopeptidase La; experience; genome sequencing; insight; macrophage; mutant; mycobacterial; pathogen; protein misfolding; residence; response; subtraction hybridization

DESCRIPTION (provided by applicant): Very little is known about the mechanisms by which pathogenic mycobacteria infect the host. In addition, there is almost no information in the literature on how the bacterium regulates gene expression in the host environment. Bacterial pathogens, which maintain long-term residence within the host cells, also need a variety of strategies to help them adapt to harsh environmental conditions. Among them is the response to stress conditions, suggesting that intracellular pathogens experience a considerable amount of protein misfolding and damage within host cells. Similarly, the regulation of mycobacterial genes and coded proteins upon interaction with the host mucosa, and within macrophages are not well known. Lon protease has been shown to participate in the regulation of stress responses in Escherichia coli. In addition to the function as scavenger of damaged proteins, Lon performs important regulatory functions by degrading cellular proteins that control gene expression. The Lon protease has also been shown to be important for Brucella abortus survival in the host. More recently, Lon has been demonstrated to regulate the expression of Salmonella invasion-related genes by proteolysis of factors required for hilA (a major regulator of the pathogenicity island 1, SP11) expression. Inactivation of Ion in Salmonella typnimurium leads to a significant increase in the ability to invade intestinal -407 epithelial cells in vitro. Inactivation of Salmonella Ion was also associated with attenuation of the bacterium in human macrophages and mice. Mycobacterium avium and M. tuberculosis interact with the host mucosa (s) at the initial stages of the infection. Upon entry into the airways and intestinal tract, gene regulation needs to occur in a rapid fashion. While a number of required genes appear to be up-regulated by conditions existing in the extra-host environment, many other genes are not. Our hypothesis is that the regulation of many mycobacterial virulence genes may likely be influenced by the action of energy dependent regulatory proteases such as Lon, i.e. using protease-mediated post-translational regulation to rapidly adapt to different conditions. Recent work using subtraction hybridization, suggests that Lon is a protein required for the efficient interaction between M. avium and the intestinal mucosa . The Ion gene is present in both M. avium and M. tuberculosis genome sequence. We, therefore, propose to gain new insight in the post-translational regulation in mycobacteria by: 1- Determining whether the overproduction and/or inactivation of Ion in M. avium (as a model organism) impacts the ability to replicate in macrophages and invade mucosal epithelial cells. This work has the potential to unveil mechanisms used by mycobacteria to regulate virulence genes in the environment of the host. In case we confirm our hypothesis, future work will address the role of Ion in M. tuberculosis

描述（由申请人提供）：关于致病性分枝杆菌感染宿主的机制知之甚少。此外，文献中几乎没有关于细菌如何调节宿主环境中基因表达的信息。细菌病原体在宿主细胞内保持长期居住，也需要各种策略来帮助它们适应恶劣的环境条件。其中之一是对应激条件的反应，表明细胞内病原体在宿主细胞内经历了相当数量的蛋白质错误折叠和损伤。类似地，分枝杆菌基因和编码蛋白在与宿主粘膜相互作用时以及在巨噬细胞内的调节也不是众所周知的。Lon蛋白酶已被证明参与调节大肠杆菌的应激反应。除了作为受损蛋白的清除剂的功能外，Lon还通过降解控制基因表达的细胞蛋白来执行重要的调节功能。Lon蛋白酶也被证明对牛种布鲁氏菌在宿主中的存活很重要。最近，已证明Lon通过蛋白水解hilA（致病性岛1，SP11的主要调节因子）表达所需的因子来调节沙门氏菌侵袭相关基因的表达。灭活鼠伤寒沙门氏菌中的离子导致体外侵入肠-407上皮细胞的能力显著增加。沙门氏菌离子的灭活也与人巨噬细胞和小鼠中细菌的衰减有关。鸟分枝杆菌和M.结核病在感染的初始阶段与宿主粘膜相互作用。一旦进入气道和肠道，基因调控需要以快速的方式发生。虽然一些必需的基因似乎是上调的条件存在于宿主外的环境中，许多其他基因不是。我们的假设是，许多分枝杆菌毒力基因的调节可能受到能量依赖性调节蛋白酶如Lon的作用的影响，即使用蛋白酶介导的翻译后调节来快速适应不同的条件。最近的工作使用减法杂交，表明Lon是一种蛋白质所需的有效相互作用之间的M。肠粘膜和肠道粘膜。Ion基因存在于M. avium和M.结核病基因组序列。因此，我们建议获得新的见解，在翻译后调节分枝杆菌：1-确定是否过量生产和/或失活的离子在M。禽流感病毒（作为模式生物）影响在巨噬细胞中复制和侵入粘膜上皮细胞的能力。这项工作有可能揭示分枝杆菌在宿主环境中调节毒力基因的机制。如果我们证实了我们的假设，未来的工作将解决离子在M中的作用。结核