Host defense functions of M. tuberculosis lipoglycan

结核分枝杆菌脂聚糖的宿主防御功能

• 批准号: 6648381
• 负责人: EDWARD D CHAN
• 金额: $ 30.42万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-15 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6648381
• 关键词: Mycobacterium tuberculosis; arabinose; cell wall; clinical research; enzyme activity; gene induction /repression; host organism interaction; human subject; immunogenetics; laboratory mouse; macrophage; mannans; microorganism immunology; mitogen activated protein kinase; nitric oxide synthase; nuclear factor kappa beta; receptor; tuberculosis; tumor necrosis factor alpha

DESCRIPTION (Adapted from the Applicant's Abstract): Tuberculosis (TB) is the leading cause of death by an infectious agent. Macrophages play a pivotal role in the control of Mycobacterium tuberculosis through the expression of nitric oxide (NO.) and TNFalpha. NO plays an important mycobactericidal role in murine TB and is increasingly recognized to be important in humans. The overall hypothesis of this proposal is that macrophages, by specific surface receptor(s), recognize mycobacterial cell wall products to initiate iNOS- and TNFa-induction. Hence, the focus of this proposal is to: i) determine the receptor and signaling mechanisms which regulate iNOS and TNFa following exposure to the mycobacterial cell wall component lipoarabinomannan (ManLAM) and ii) to determine the significance of each of these components in an in vitro model of infection. Based on experiments showing that macrophages from the Toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice produced significantly lower levels of NO than TLR4-intact C3H/HeN macrophages in response to IFNg + ManLAM, we hypothesize that ManLAM engages a TLR to induce iNOS-NO*/ TNFa expression. Since non-mannose capped LAM (AraLAM) from M. smegmatis induced greater NO about expression than ManLAM, we hypothesize that ii) the exposed arabinose residues on ManLAM or AraLAM are the components of ManLAM that bind to its putative TLR. Since initial studies show that the mitogen-activated protein kinases (MAPKs) and NFkB signaling pathways regulate iNOS and TNFa expression, we hypothesize that the proximal kinase MAP/ERK kinase kinase (MEKK) is a pivotal regulator for ManLAM-induction of iNOS and TNFa. Lastly, because TLRs recognize pathogen-derived molecules and enhance host-defenses, we hypothesize that blocking one or more of the TLRs will enhance the growth of M. tuberculosis and inhibit NO* and TNFa expression. These hypotheses will be addressed by three specific aims: 1. To determine the ManLAM structures that mediate the induction of iNOS-NO*/TNFa and the receptor that mediates these ManLAM effects. 2. To investigate the role of the MAPK and NFkB signaling pathways in ManLAM- and other lipoglycan-induced iNOS-NO* and TNFa. 3. To elucidate the role of the TLRs, MAPK and NFkB signaling pathways, and ManLAM in controlling the growth of M. tuberculosis in mouse and human macrophages and to correlate effects on growth with NO* and TNFa expression.

描述（改编自申请人的摘要）：结核病（TB）是 传染性病原体导致的主要死亡原因宏观经济发挥着关键作用 通过表达一氧化氮来控制结核分枝杆菌 氧化物（NO.）和TNF α。NO在小鼠体内具有重要的杀菌作用 越来越多的人认识到结核病对人类的重要性。整体 该建议的假设是巨噬细胞通过比表面 受体，识别分枝杆菌细胞壁产物以启动iNOS-和 TNF α诱导。因此，本建议的重点是： 受体和信号传导机制，调节iNOS和TNF α， 暴露于分枝杆菌细胞壁组分脂阿拉伯甘露聚糖（ManLAM） 以及ii）确定这些分量中的每一个在一个 体外感染模型。基于实验表明， Toll样受体4（TLR 4）突变C3 H/HeJ小鼠产生显著的 响应IFNg +，NO水平低于TLR 4-完整的C3 H/HeN巨噬细胞 ManLAM，我们假设ManLAM与TLR结合以诱导iNOS-NO*/TNF α， 表情由于非甘露糖封端的LAM（AraLAM）来自M.磺胺嘧啶诱导的 比ManLAM更大的NO表达，我们假设ii）暴露的 ManLAM或AraLAM上的阿拉伯糖残基是ManLAM的组分， 其假定的TLR。因为最初的研究表明， 蛋白激酶（MAPKs）和NF κ B信号通路调节iNOS和TNF α 表达，我们假设近端激酶MAP/ERK激酶激酶 MEKK是ManLAM诱导iNOS和TNF α的关键调节因子。最后， 由于TLR识别病原体衍生的分子并增强宿主防御， 假设阻断一个或多个TLR将增强M的生长。 抑制NO* 和TNF α的表达。这些假设将是 有三个具体目标：1。为了确定ManLAM结构， 介导iNOS-NO*/TNF α的诱导以及介导这些的受体 ManLAM效果。2.探讨MAPK和NF κ B信号通路在细胞凋亡中的作用， 在ManLAM-和其他脂聚糖诱导的iNOS-NO* 和TNF α途径中。3.到 阐明TLR、MAPK和NFkB信号通路以及ManLAM在 控制M.小鼠和人巨噬细胞中的结核病， 将对生长的影响与NO* 和TNF α表达相关联。