MODULATION OF INNATE IMMUNE DEFENSES BY MYCOBACTERIUM TUBERCULOSIS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 结核病仍然是全球公共卫生的主要威胁，据估计，结核分枝杆菌感染每年导致200多万人死亡。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是如何逃避天然免疫并在恶劣的免疫环境中生存的。结核分枝杆菌发病机制的一个主要特征是它能够在巨噬细胞内生长，调节其活动并干扰杀菌功能。我们已经确定了一种编码丝氨酸水解酶的细胞膜定位的脂蛋白Rv2224c，它对结核分枝杆菌在体内的毒力、在巨噬细胞中的存活和对细胞膜定向应激的抵抗至关重要。我们将这个蛋白命名为Hip1(水解酶对发病机制1很重要)。我们证明，Hip1抑制先天免疫反应；Hip1突变在巨噬细胞Toll样受体(TLR)信号下游诱导增强的促炎反应。我们假设Hip1通过修饰细胞膜或分泌底物来调节先天免疫和宿主防御。本项目的重点是了解Hip1如何抑制宿主的先天免疫途径，并确定Hip1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.