MODULATION OF INNATE IMMUNE DEFENSES BY MYCOBACTERIUM TUBERCULOSIS

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。 结核病（TB）仍然是对全球公共卫生的主要威胁，估计结核分枝杆菌（Mtb）感染每年导致超过200万人死亡。为了开发新的结核病疫苗和药物，我们需要了解结核分枝杆菌如何逃避先天免疫并在不利的免疫环境中生存。Mtb发病机制的中心特征是其在巨噬细胞内生长、调节其活性并干扰杀微生物功能的能力。我们已经确定了一个细胞定位的脂蛋白编码的丝氨酸水解酶，Rv 2224 c，这是至关重要的结核分枝杆菌在体内的毒力，在巨噬细胞中的生存和抵抗细胞凋亡定向应力。我们将这种蛋白质命名为Hip 1（Hydrolase important for pathogenesis 1）。我们证明，Hip 1抑制先天性免疫反应; Hip 1突变体诱导增强巨噬细胞Toll样受体（TLR）信号下游的促炎反应。我们推测，Hip 1修改细胞包膜或分泌底物，以调节先天免疫和宿主防御。该项目的重点是了解Hip 1如何抑制宿主先天免疫途径，并确定Hip 1功能的分子和生化机制。

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. Tuberculosis (TB) remains a major threat to global public health and infection with Mycobacterium tuberculosis (Mtb) is estimated to result in over 2 million deaths annually. In order to develop new vaccines and drugs for TB, we need to understand how Mtb evades innate immunity and survives in hostile immune environments. A central feature of Mtb pathogenesis is its ability to grow within macrophages, modulate their activities and interfere with microbicidal functions. We have identified a cell envelope-localized lipoprotein encoding a serine hydrolase, Rv2224c, which is critical for Mtb virulence in vivo, survival in macrophages and resistance to cell envelope-directed stresses. We have named this protein Hip1 (Hydrolase important for pathogenesis 1). We demonstrate that Hip1 suppresses innate immune responses; hip1 mutants induce enhanced proinflammatory responses downstream of Toll-like receptor (TLR)-signaling in macrophages. We hypothesize that Hip1 modifies cell envelope or secreted substrates to modulate innate immunity and host defense. The focus of this project is to understand how Hip1 suppresses host innate immune pathways and determine the molecular and biochemical mechanisms for Hip1 function.