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

• 批准号: 7914752
• 负责人: Jordi B Torrelles
• 金额: $ 25.8万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914752
• 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

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.

当通过空中传播发生结核分枝杆菌（M.TB）感染时，杆菌沉积在肺的肺泡空间中。在肺泡空间内，近端存在许多先天免疫机制，这些机制对于维持肺稳态至关重要。 M.TB是巨噬细胞的高度宿主适应的细胞内病原体，可以在感染过程中使用这些机制来提高其优势。关于M.TB如何受到巨噬细胞外肺泡微环境中遇到的免疫压力的影响知之甚少。除肺泡巨噬细胞外，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，及其分泌的产物（即表面活性剂）。这些肺泡隔室中的每一个都包含其独特的水解酶阵列，这些水解酶释放到肺泡环境中并在表面活性剂中隔离。当M.TB最初沉积在末端支气管和肺泡中，以及随后从裂解的巨噬细胞中释放出来时，杆菌与这些水解酶密切接触。在K99/R00 NIH独立奖奖中，Torrelles博士将研究人类肺泡环境对M.TB细胞包膜的影响，以及这些影响如何决定宿主内M.TB的命运。使用标记的毒力M.TB H37RV和/或M.TB Erdman，以及生化，分子和细胞生物学方法，我们提出：1）表征源自肺泡隔室细胞和肺表面活性剂的特定水解酶，这些水解酶影响毒力型M.TB的细胞包膜。为了确保研究保持专注，我们将优先考虑候选水解酶，并将实验限制为对3-5个水解酶的研究； 2）表征我们选择的人类肺水解酶对毒物M.TB细胞包膜完整性的影响； 3）为确定毒力型M.TB细胞包膜上的水解酶衍生的修饰如何影响肺泡隔室细胞内的太阳/IVAR。