In vivo regulation of M. tuberculosis cell wall lipids

这是一份正在考虑资助的提案申请的修订摘要 通过《美国复苏和再投资法案》。这个项目的目标是 描述与潜伏结核病相关的结核分枝杆菌操纵子MCEL的作用 感染。这个项目是基于一个新的假设，即结核分枝杆菌需要 适应宿主肉芽肿性病变不断变化的环境 细菌就栖息在那里。我们有证据表明这种肉芽肿内适应是 由结核分枝杆菌介导的细胞膜信号重塑 由凋亡的细胞产生。我们认为这种重塑是由mcel调节的。 结核分枝杆菌操纵子。此前的研究表明，一种结核分枝杆菌菌株 被破坏的mcel操纵子在小鼠中变得超强毒力，无法详细说明 小鼠肺部有组织的肉芽肿。一株结核分枝杆菌菌株在 这种被称为mcel R的操纵子的负调控因子在小鼠身上也是超强毒力的。与 前突变体，小鼠因细菌繁殖失控而死亡 后来，小鼠死于不受控制的炎症。因此，这两个极端 免疫活性小鼠肉芽肿相关临床结局 影响mcel操纵子基因的表达。这表明这部操纵剧 在肉芽肿形成过程中的动态平衡作用。结核分枝杆菌包含3个其他 Mce操纵子的成员称为mce2、3和4。mce3和mce4突变体具有 在小鼠身上进行了测试，它们表现出与mcel操纵子不同的表型。 突变--它们在老鼠身上变弱了。因此，4个MCE操纵子的功能可以 各有不同，但也可能是相关的。本项目修订后的2年期的具体目标 项目是将mcel操纵子的功能表征为可能的脂类运输。 系统或调节器及其对结核分枝杆菌细胞重塑的影响 包膜对肉芽肿细胞周转的反应为芽孢杆菌感染。 前面的附加目的是表征MCE1操纵子与MCE2的关系， 3和4个操作子将在支持机制下完成，我们计划在 这个项目的第二年。我们相信这种对M。 结核和肉芽肿可能有助于我们了解其发病机制。 结核分枝杆菌的持久性可能导致新的测试来区分活动性结核病和 潜伏的结核病感染。

This is a revised abstract of an application of a proposal being considered for funding through the American Recovery and Reinvestment Act. The goal of this project is to characterize the role of an M. tuberculosis operon called mcel associated with latent TB infection. This project is based on a new hypothesis that M. tuberculosis needs to readapt to the constantly changing environment of the host granulomatous lesion in which the bacilli reside. We have evidence that this intra-granuloma adaptation is mediated by M. tuberculosis remodeling its cell envelope in response to signals produced by apoptotic cells. We propose that this remodeling is regulated by the mcel operon of M. tuberculosis. Previous studies have shown that an M. tuberculosis strain disrupted in the mcel operon becomes hypervirulent in mice and is unable to elaborate organized granulomas in mouse lungs. An M. tuberculosis strain disrupted in the negative regulator of this operon called mcel R is also hypervirulent in mice. With the former mutant, mouse dies because of uncontrolled bacterial proliferation while with the latter, the mouse dies because of uncontrolled inflammation. Thus, these two extreme granuloma-related clinical outcomes in immunocompetent mice are induced simply by affecting the expression of the mcel operon genes. This suggests that this operon plays a homeostatic role in response to granuloma formation. M. tuberculosis contains 3 other members of this mce operon called mce2, 3, and 4. The mce3 and mce4 mutants have been tested in mice, and they show a phenotype distinct from that of the mcel operon mutant--they are attenuated in mice. Thus, the functions of the 4 mce operons may vary, but they may also be related. The specific aim of this project for the revised 2-year project is to characterize the function of the mcel operon as a possible lipid transport system or regulator and how this may contribute to remodeling M. tuberculosis cell envelope in response to granuloma cell turnover for the bacillus to establish infection. The previous additional aim to characterize the relationship of the mcel operon to mce2, 3, and 4 operons will be done under a support mechanism to which we plan to apply in Yr 2 of this project. We believe this characterization of the relationship between M. tuberculosis and granulomas may contribute to our understanding of the mechanism of persistence of M. tuberculosis that could lead to new tests to differentiate active TB from latent TB infection.