THE CRUCIAL ROLE OF M TUBERCULOSIS SIGMA-H IN IMMUNOPATHOLOGY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 监管级联涉及几个不同的 这些因素使得结核分枝杆菌（Mtb）在感染期间有效地适应环境变化。Sigma H在热、巯基氧化应激和吞噬作用下被诱导。在恒河猴中研究了与Mtb-sigma H突变体相关的“尽管组织持久性相当但免疫病理学降低”表型。感染Mtb的动物发展为活动性TB，其特征在于广泛的肺肉芽肿组织病理学，而感染突变体的动物在可辨别的杆菌生长之后表现出减少的病理学。我们试图了解在结核分枝杆菌感染期间西格玛H引起免疫病理学的分子机制。最近，我们已经证明sigma^H控制的基因和调节子的表达远大于预期数量，包括ATP依赖性Clp蛋白水解复合物、Mce 1毒力调节子、抗凋亡nuoA-G操纵子等。脂质代谢的系统性减少，包括分枝杆菌酸、分枝杆菌素铁载体和聚酮化合物的生物合成，与sigma H驱动的Clp蛋白水解诱导相一致。我们推测，关键的，限速酶从脂质生物合成途径的选择性目标的Clp蛋白水解降解。我们目前正在验证这一假设。我们正在研究FoxP 3标记的调节性T细胞和表达颗粒酶B的溶细胞性T细胞作为免疫病理学介质。在突变体的背景下研究宿主-Mtb相互作用提供了一个解剖导致免疫病理学的信号级联的机会。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 s factors 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 "reduced immunopathology in spite of comparable tissue persistence" phenotype associated with the Mtb-sigma H mutant was studied in rhesus macaques. Animals infected with Mtb developed active TB, characterized by extensive lung granulomatous histopathology, while animals infected with the mutant exhibited reduced pathology, in the wake of discernible bacillary growth. We seek to understand the molecular mechanisms by which sigma H causes immunopathology during Mtb infection. Recently, we have shown that sigma^H controls the expression of a much larger than anticipated number of genes and regulons, including the ATP-dependent Clp proteolysis complex, the Mce1 virulence regulon, the anti-apoptotic nuoA-G operon, etc. A systemic reduction in lipid metabolism including biosynthesis of mycolic acids, mycobactin siderophores and polyketides coincides with the sigma H driven induction of Clp proteolysis. We hypothesize that key, rate-limiting enzymes from lipid biosynthetic pathways are the selective targets of Clp proteolytic degradation. We are currently testing this hypothesis. We are looking at FoxP3 marked T regulatory cells and Granzyme B expressing cytolytic T cells as mediators of immunopathology. Studying host-Mtb interactions in the context of the 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.