THE CRUCIAL ROLE OF M TUBERCULOSIS SIGMA-H IN IMMUNOPATHOLOGY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 涉及几个不同的西格玛因子之一的调节级联可能使结核分枝杆菌(Mtb)能够有效地适应感染期间的环境变化。Sigma H是在热、硫醇氧化应激和吞噬作用下诱导的。我们最近在恒河猴身上证实了与Mtb-sigma H突变相关的独特的“尽管具有类似的组织持久性，但免疫病理减少”的表型。感染结核分枝杆菌的动物出现活动性结核病，其特征是广泛的肺肉芽肿性组织病理学，而感染Sigma H突变的动物在类似的细菌负担之后表现出显著的病理减轻。我们现在试图了解SigmaH在结核分枝杆菌感染过程中引起免疫病理的分子机制。在没有Sigma H的情况下，硫氧还蛋白调节子和CLP蛋白分解机制的诱导受到影响。参与招募和激活免疫效应细胞的几种Mtb蛋白被宿主的氧化爆发所破坏。我们推测，这些氧化蛋白现在在激发效应细胞和刺激细胞因子/趋化因子介导的信号级联反应方面效率低下，显然是因为在Delta-sigma H突变体中缺乏硫氧还蛋白-硫氧还蛋白还原酶和CLP蛋白水解酶的诱导水平。我们进一步假设，这些缺陷损害了突变体引起免疫病理的能力。相反，在感染结核分枝杆菌后，一个或多个Sigma H依赖因子与宿主免疫系统相互作用，并刺激宿主免疫系统造成免疫病理损害。在Delta-sigma H突变的背景下研究宿主-Mtb的相互作用为剖析导致免疫病理的信号级联反应提供了机会。这些知识可能为未来结核病的控制和治疗开辟新的途径。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Regulatory cascades involving one of the several different sigma factors likely allows Mycobacterium tuberculosis (Mtb) to efficiently adapt to environmental changes during infection. sigma H is induced in response to heat, thiol-oxidative stress and phagocytosis. The unique "reduced immunopathology in spite of comparable tissue persistence" phenotype associated with the Mtb-sigma H mutant has recently been verified by us in rhesus macaques. Animals infected with Mtb developed active TB, characterized by extensive lung granulomatous histopathology, while animals infected with the sigma H mutant exhibited markedly reduced pathology, in the wake of comparable bacillary burden. We now seek to understand the molecular mechanisms by which sigmaH causes immunopathology during Mtb infection. In absence of sigma H, induction of thioredoxin regulon and Clp proteolytic machinery is compromised. Several Mtb proteins involved in recruiting and activating immune effector cells are damaged by the host oxidative burst. We hypothesize that these oxidized proteins are now inefficient at eliciting effector cells and stimulating cytokine/chemokine-mediated signaling cascades, apparently, due to the lack of induced levels of thioredoxin-thioredoxin reductase and Clp proteases, in the delta-sigma H mutant. We further hypothesize that these deficiencies impair the mutant's ability to cause immunopathology. Conversely, upon infection with Mtb, one or more sigma H-dependent factors interact with and provoke the host immune system into causing immunopathological damage. Studying host-Mtb interactions in the context of the delta-sigma H mutant offer a chance to dissect the signaling cascades that lead to immunopathology. Such knowledge may open new avenues towards the future control and therapeutics of TB.