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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的结核分枝杆菌（MTB）是人类病原体，会引起明显的发病率和死亡率全世界。越来越多的结核病病例是由多药和极端耐药性引起的 MTB菌株强调了对新型治疗的需求。 MTB操纵感染的细胞以实现毒力和此目的MTB需要分泌蛋白质，这将与宿主细胞相互作用。第一个类型7 分泌系统（T7SS）最初在分枝杆菌中鉴定已描述（ESX-1至ESX-5）。 ESX-5系统的核心四个基因序列已重复在MTB基因组（ESX-5A，ESX-5B和ESX-5C）中三次。在这里，我们提出了一个新的假设重复的ESX-5区域在ESX-5分泌的特定亚组的分泌中具有附属功能蛋白质。在AIM1中，我们计划生成MTB缺失突变体，以确定删除的影响 ESX-5辅助系统有关宿主细胞反应和毒力。在AIM2中，我们将使用蛋白质组学表征与ESX-5附件系统相关的秘密组的方法。这些研究会奠定基础，以识别特定的ESX-5分泌，效应子蛋白对MTB至关重要毒力。因此，拟议的研究最终将有助于设计更好的重组疫苗菌株和/或一代人的药物开发目标。