Mtb regulators of essential and virulence-associated MmpLs

必需 MmpL 和毒力相关 MmpL 的 Mtb 调节因子

• 批准号: 9106596
• 负责人: Georgiana E. Purdy
• 金额: $ 47.64万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9106596
• 关键词: 1,2-diacylglycerol; Algorithms; Antibiotics; Bacteria; Binding; Binding Sites; Carbon; Carrier Proteins; Cause of Death; Cell Wall; Cells; ChIP-seq; Chronic; Communicable Diseases; Computer Simulation; Consensus; DNA; DNA Binding; DNA-Protein Interaction; DNase-I Footprinting; Data; Diglycerides; Docking; Electrophoretic Mobility Shift Assay; Esters; Fatty Acids; Gene Expression; Gene Expression Regulation; Genes; Health; Immune; Immune response; In Vitro; Infection; Ligand Binding; Ligands; Lipids; Maintenance; Membrane Proteins; Metabolic; Microbial Biofilms; Modeling; Molecular; Mycobacterium tuberculosis; Mycolic Acid; Nucleic Acid Regulatory Sequences; Nutrient; Oxidative Stress; Pathogenesis; Patients; Physiology; Play; Protein Export Pathway; Proteins; Regulation; Regulon; Resistance; Role; Site-Directed Mutagenesis; Source; Staging; Stimulus; Stress; Structure; System; Therapeutic; Transcriptional Regulation; Trehalose; Tuberculosis; Virulence; Waxes; Work; clinically relevant; combat; insight; interest; lipid biosynthesis; lipid transport; mycobacterial; mycolate; novel; overexpression; pathogen; protein expression; protein transport; small molecule; transcription factor; tuberculosis granuloma

 DESCRIPTION (provided by applicant): Despite the availability of antibiotics to combat Tuberculosis (TB), it is one of the leading causes of death due to infectious disease. Mycobacterium tuberculosis (Mtb) is a successful pathogen because it survives within immune cells and effectively establishes and maintains a latent TB infection. Therefore, understanding the mechanisms underlying the establishment or maintenance of dormancy can inform new strategies for TB therapeutics. Mycobacterial membrane protein large (MmpL) proteins are dedicated cell wall lipid transporters. Along with their accessory Mycobacterial membrane protein small (MmpS) proteins, these transporters are crucial players in mycobacterial physiology and pathogenesis. MmpL3 is essential; and MmpL4, MmpL5, MmpL7, MmpL8, MmpL10 and MmpL11 contribute to Mtb virulence. The function of the related proteins MmpL3 and MmpL11 that transport mycolic acid-containing lipids are of particular interest to us. MmpL3 transports trehalose monomycolate and is required for mycobacterial replication and viability. We showed that MmpL11 transports monomeromycolyl diacylglycerol and a mycolate ester wax. These are species of lipids that are sometimes referred to as "storage lipids" and are associated with dormant bacteria in vitro and accumulate in granulomas of TB patients. Therefore, it appears that MmpL11 plays a role in a clinically relevant, but poorly understood, aspect of Mtb pathogenesis. While significant advances have been made identifying MmpL substrates, the regulation of MmpL protein expression and their role in cell wall remodeling in different environmental conditions has not been explored. The proposed studies will characterize the structure and function of Mtb transcriptional regulators that control expression of essential and virulence-associated MmpL and MmpS proteins. Our preliminary data indicate that fatty acids directly modulate activity of some transcription factors. This suggests a model where Mtb can directly assess and respond to fatty acid intermediates, metabolic state and nutrient availability to control mmpL and mmpS gene regulation. By defining the molecular mechanisms underlying the regulation of MmpL transporters and identifying their regulons, we will generate novel insights into the transition between actively dividing Mtb and latent or non-replicating persistent Mtb.

 描述（由申请人提供）：尽管可以使用抗生素来对抗结核病（TB），但它仍然是传染病导致死亡的主要原因之一。结核分枝杆菌 (Mtb) 是一种成功的病原体，因为它能在免疫细胞内存活并有效地建立和维持潜伏性结核感染。因此，了解休眠建立或维持的机制可以为结核病治疗的新策略提供信息。 分枝杆菌大膜蛋白 (MmpL) 是专用的细胞壁脂质转运蛋白。这些转运蛋白与其附属的分枝杆菌小膜蛋白 (MmpS) 一起，在分枝杆菌生理学和发病机制中发挥着至关重要的作用。 MmpL3 必不可少； MmpL4、MmpL5、MmpL7、MmpL8、MmpL10 和 MmpL11 有助于 Mtb 毒力。我们对运输含分枝菌酸脂质的相关蛋白 MmpL3 和 MmpL11 的功能特别感兴趣。 MmpL3 转运海藻糖单分枝菌酯，是分枝杆菌复制和活力所必需的。我们发现 MmpL11 转运单体菌基二酰基甘油和霉菌酸酯蜡。这些脂质有时被称为“储存脂质”，与体外休眠细菌相关，并在结核病患者的肉芽肿中积聚。因此，MmpL11 似乎在 Mtb 发病机制的一个临床相关但知之甚少的方面发挥着作用。 虽然在识别 MmpL 底物方面取得了重大进展，但 MmpL 蛋白表达的调节及其在不同环境条件下细胞壁重塑中的作用尚未得到探索。拟议的研究将表征 Mtb 转录调节因子的结构和功能，这些转录调节因子控制必需的和毒力相关的 MmpL 和 MmpS 蛋白的表达。我们的初步数据表明脂肪酸直接调节一些转录因子的活性。这表明 Mtb 可以直接评估和响应脂肪酸中间体、代谢状态和营养可用性，以控制 mmpL 和 mmpS 基因调控。通过定义 MmpL 转运蛋白调节的分子机制并识别其调节子，我们将对活跃分裂的 Mtb 和潜伏或非复制持久性 Mtb 之间的转变产生新的见解。