THE CRUCIAL ROLE OF M TUBERCULOSIS SIGMA-H IN IMMUNOPATHOLOGY

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 涉及几种不同δ因子之一的调节级联允许结核分枝杆菌（Mtb）在感染期间有效地适应环境变化。SigmaH在热、巯基氧化应激和吞噬作用下被诱导。Mtb delta-sigH突变体在小鼠中的生长是减毒的。我们试图了解Δ SigmaH在Mtb感染期间引起免疫病理学的分子机制。我们发现SigH与SigE、SigB和ClgR形成了一个转录网络，ClgR是Mtb中Clp基因调节子的调节因子（1）。这个网络对细胞被膜损伤有反应。Mtb而不是Δ sigH和Δ sigE突变体能够抵抗这种包膜损伤（1）。SigB的化学过表达能够逆转对包膜损伤的超易感性（1）。我们还表明，SigH的表达不仅在热和氧化应激反应中被诱导，而且在非抗生素化合物硫利达嗪（THZ）反应中也被诱导，这会导致包膜损伤（2）。在delta-sigH突变体中，诱导无效（2）。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。我们还表明，感染恒河猴衍生的骨髓巨噬细胞（BMDM）的delta-sigH突变体的结果在较高的细胞凋亡和δ趋化因子分泌相对于感染结核分枝杆菌。用Mtb的气溶胶体内感染恒河猴导致快速肺结核。促炎细胞因子和趋化因子对这种感染的反应在第4周达到峰值，并在第13周重新编程（3）。然而，这些动物不能存活超过13周。我们发现，动物感染delta-sigH突变体后表现出完全减毒的表型。我们现在正在研究对这种感染的免疫反应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Regulatory cascades involving one of the several different delta factors allows Mycobacterium tuberculosis (Mtb) to efficiently adapt to environmental changes during infection. SigmaH is induced in response to heat, thiol-oxidative stress and phagocytosis. The Mtb delta-sigH mutant is attenuated for growth in mice. We seek to understand the molecular mechanisms by which delta SigmaH causes immunopathology during Mtb infection. We showed that SigH forms a transcriptional network with SigE, SigB and ClgR, the regulator for Clp gene regulon in Mtb (1). This network responds to cell-envelope damage. Mtb, but not the delta sigH and delta sigE mutants are able to resist this envelope damage (1). Chemical over-expression of SigB is able to reverse the hyper-susceptibility to envelope damage (1). We also show that the expression of SigH is not only induced in response to heat and oxidative stress but also in response to a non-antibiotic compound, thioridazine (THZ), which causes envelope damage (2). The induction is nullified in the delta-sigH mutant (2). Studying host-Mtb interactions in the context of the mutant offers a chance to dissect the signaling cascades that lead to immunopathology. We also show that infection of rhesus derived bone marrow macrophages (BMDMs) with the delta-sigH mutant results in higher apoptosis and delta chemokine secretion relative to infection with Mtb. In-vivo infection of rhesus macaques with the aerosols of Mtb causes rapid pulmonary TB. The pro-inflammatory cytokine and chemokine response to this infection peaks at 4 weeks and reprograms by week 13 (3). However, the animals don't survive beyond week 13. We show that animals comparably infected with the delta-sigH mutant exhibit a completely attenuated phenotype. We are now studying the immune response to this infection.