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Remodeling of the M. tuberculosis cell wall by the host microenvironment

宿主微环境对结核分枝杆菌细胞壁的重塑

基本信息

批准号：
7929620
负责人：
Jordi B Torrelles
金额：
$ 30.31万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929620
关键词：
Acetates Affect Alveolar Alveolar Macrophages Alveolus Award Bacillus (bacterium)Bacteria Biochemical Bronchoalveolar Lavage Fluid Cell Wall Cells Cellular biology Cytolysis Data Quality Deposition Drug Delivery Systems Ensure Environment Epithelial Epithelial Cells Genus Mycobacterium Glucose Homeostasis Human Hydrolase Immune Immune response Infection Label Lung Mass Spectrum Analysis Metabolism Methods Modification Molecular Mycobacterium tuberculosis Myeloid Cells Pathway interactions Pulmonary Surfactants Radiolabeled Shapes Source Staining method Stains Surface Terminal Bronchiole The Sun United States National Institutes of Health Virulent base cell envelope improved in vitro Model macrophage mass spectrometer monocyte neutrophil novel pathogen pressure radiotracer receptor research study response surfactant transmission process

项目摘要

When Mycobacterium tuberculosis (M.tb) infection occurs by airiaorne transmission, bacilli are deposited in the alveolar spaces of the lungs. Within the alveolar space and proximal to it exist a number of innate immune mechanisms that are critical in maintaining pulmonary homeostasis. M.tb, a highly host-adapted intracellular pathogen of macrophages, may use these mechanisms to its advantage during infection. Little is known about how M.tb is affected by the immune pressure that it encounters in the alveolar microenvironment outside of the macrophage. In addition to alveolar macrophages, major constituents of lung defense in the alveolar space are type I and II epithelial cells, monocytes, and neutrophils, and their secreted products to the alveolar lumen (I.e., surfactant). Each of these alveolar compartment cells contains its own unique array of hydrolases that are released to the alveolar environment and sequestered in surfactant. When M.tb is initially deposited in the terminal bronchioles and alveoli, as well as following release from lysed macrophages, the bacilli are in close contact with these hydrolases. During the K99/R00 NIH Pathway to Independence Award, Dr. Torrelles will examine the effects of the human alveolar environment on the cell envelope of M.tb and how these effects dictate the fate of M.tb within the host. Using labeled virulent M.tb H37Rv and/or M.tb Erdman, and biochemical, molecular and cell biology approaches, we propose: 1) To characterize specific hydrolases derived from alveolar compartment cells and pulmonary surfactant that affect the cell envelope of virulent M.tb. To ensure that the studies remain focused, we will prioritize candidate hydrolases and restrict our experiments to the study of the 3-5 hydrolases in total; 2) To characterize the effects of our selected human lung hydrolases on the integrity of the virulent M.tb cell envelope; and 3) To determine how hydrolase-derived modifications on the cell envelope of virulent M.tb affect the bacillus sun/ival within alveolar compartment cells.

当结核分枝杆菌（M.tb）感染通过空气传播发生时，杆菌沉积在肺的肺泡腔中。在肺泡腔内及其近端存在许多先天免疫机制，这些机制在维持肺内稳态中至关重要。结核分枝杆菌是一种高度适应宿主的巨噬细胞内病原体，在感染过程中可能利用这些机制发挥其优势。关于结核分枝杆菌如何受到巨噬细胞外肺泡微环境中免疫压力的影响，人们知之甚少。除了肺泡巨噬细胞之外，肺泡空间中肺防御的主要成分是I型和II型上皮细胞、单核细胞和嗜中性粒细胞，以及它们分泌到肺泡腔的产物（即，表面活性剂）。这些肺泡隔室细胞中的每一个都含有其自身独特的水解酶阵列，这些水解酶被释放到肺泡环境中并被隔离在表面活性剂中。当结核分枝杆菌最初沉积在终末细支气管和肺泡中时，以及从裂解的巨噬细胞释放后，杆菌与这些水解酶密切接触。在K99/R 00 NIH独立之路奖期间，Torrelles博士将研究人类肺泡环境对结核分枝杆菌细胞包膜的影响，以及这些影响如何决定结核分枝杆菌在宿主体内的命运。利用标记的强毒M.tbH37Rv和/或M. tbErdman，以及生物化学、分子生物学和细胞生物学方法，我们提出：1）表征来自肺泡隔室细胞的特异性水解酶和肺表面活性物质，它们影响强毒M. tb的细胞被膜。为了确保研究保持集中，我们将优先考虑候选水解酶，并将我们的实验限制为总共3-5种水解酶的研究; 2）表征我们选择的人肺水解酶对毒性结核分枝杆菌细胞包膜完整性的影响;和3）为了确定在毒性结核分枝杆菌的细胞包膜上的水解酶衍生的修饰如何影响芽孢杆菌sun/在肺泡隔室细胞内存活。