Characterization of the ESX-5 secretome and its impact on virulence mechanisms of Mycobacterium tuberculosis

ESX-5 分泌组的表征及其对结核分枝杆菌毒力机制的影响

• 批准号: 9333513
• 负责人: VOLKER BRIKEN
• 金额: $ 22.72万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-14 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333513
• 关键词: Aerosols; Bacteria; Cathepsins B; Cell Death; Cell Death Induction; Cell Fraction; Cell Surface Proteins; Cell surface; Cells; Cessation of life; Collecting Cell; Communities; Complement; Drug Design; Drug resistance in tuberculosis; ELF3 gene; Filtration; Future; Generations; Genes; Genome; Genus Mycobacterium; Histopathology; Human; Individual; Infection; Inflammasome; Inflammatory; Interleukin-1 beta; Liver; Lung; Mass Spectrum Analysis; Measures; Mediating; Molecular; Molecular Chaperones; Morbidity - disease rate; Mus; Mycobacterium marinum; Mycobacterium tuberculosis; Parents; Pathway interactions; Pharmaceutical Preparations; Phenotype; Protein Secretion; Proteins; Proteomics; Recombinant Vaccines; Research; Research Project Grants; Resources; SCID Mice; Spleen; Subgroup; Surface; System; Testing; Time; Tuberculosis; Vaccines; Virulence; Virulence Factors; Wild Type Mouse; carboxypeptidase C; cytokine; design; drug development; improved; in vivo; mortality; mouse model; mutant; new therapeutic target; novel; novel therapeutics; pathogen; response

Abstract Mycobacterium tuberculosis (Mtb) is a human pathogen that causes significant morbidity and mortality worldwide. An increasing number of tuberculosis cases are caused by multi-drug and extreme-drug resistant Mtb strains, underscoring the need for novel therapeutics. Mtb manipulates infected cells in order to achieve virulence and to this end Mtb needs to secrete proteins, which will interact with the host cell. The first type 7 secretion system (T7SS) was originally identified in mycobacteria and since then four additional systems have been described (ESX-1 through ESX-5). A core, four-gene sequence of the ESX-5 system has been duplicated three times in the Mtb genome (ESX-5a, ESX-5b and ESX-5c). Here we propose the novel hypothesis that the duplicated ESX-5 regions have an accessory function in the secretion of specific subgroups of ESX-5-secreted proteins. In AIM1 we plan to generate Mtb deletion mutants in order to determine the impact of the deletion of the ESX-5 accessory systems on host cell responses and virulence. In AIM2 we will use proteomics approaches to characterize the secretomes associate with the ESX-5 accessory systems. These studies will lay the groundwork to enable the identification of specific, ESX-5-secreted, effector proteins critical for Mtb virulence. The proposed research will thus ultimately aid in the design of better recombinant vaccines strains and/or the generation novel targets for drug development.

摘要 结核分枝杆菌（Mycobacterium tuberculosis，Mtb）是一种引起严重发病和死亡的人类病原体 国际吧越来越多的结核病病例是由多重耐药和极端耐药引起的。 结核分枝杆菌菌株，强调需要新的治疗。结核分枝杆菌操纵受感染的细胞， 因此，Mtb需要分泌与宿主细胞相互作用的蛋白质。第一种类型7 分泌系统（T7 SS）最初在分枝杆菌中被鉴定，此后又有四个额外的系统， （ESX-1到ESX-5）。ESX-5系统的核心四基因序列已被复制 在Mtb基因组中有三次（ESX-5a、ESX-5 b和ESX-5c）。在这里，我们提出了一个新的假设， 复制的ESX-5区域在ESX-5分泌的特定亚群的分泌中具有辅助功能。 proteins.在AIM 1中，我们计划产生Mtb缺失突变体，以确定Mtb缺失的影响。 ESX-5辅助系统对宿主细胞反应和毒力的影响。在AIM 2中，我们将使用蛋白质组学 表征与ESX-5附件系统相关的分泌组的方法。这些研究将 为鉴定特异性、ESX-5分泌的、对结核分枝杆菌至关重要的效应蛋白奠定基础 毒性因此，拟议中的研究将最终有助于设计更好的重组疫苗菌株。 和/或产生用于药物开发的新靶点。