ROLE OF MYCOBACTERIUM TUBERCULOSIS PROTEASE IN PATHOGENESIS AND HOST RESPONSE

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。 结核分枝杆菌是一种非常成功的人类病原体，它已经进化成在宿主体内生存。我们的长期目标是阐明结核分枝杆菌干扰巨噬细胞杀菌功能和逃避宿主免疫反应的机制。了解结核分枝杆菌与宿主相互作用的分子机制对于设计治疗干预措施和疫苗策略非常重要。我们已经确定Rv2224c是一种预测的蛋白酶，对巨噬细胞和体内的生存至关重要。我们推测Rv2224c是一种重要的毒力因子，它能分解结核分枝杆菌的底物，调节宿主的免疫反应。虽然蛋白水解酶被认为是其他细菌病原体的关键毒力因子，但蛋白水解酶在结核分枝杆菌致病机制中的作用在很大程度上尚不清楚。我们的初步研究表明，Rv2224c输出到分枝杆菌的细胞膜上。被破坏的蛋白水解酶突变体会损害巨噬细胞和体内的生长。与野生型感染的小鼠相比，感染了蛋白酶突变体的小鼠的肺部病理明显减轻，存活时间更长，我们有新的证据表明Rv2224c调节宿主的先天免疫。 更新2010我们已经证明Rv2224c抑制先天免疫反应；Rv2224c突变诱导巨噬细胞Toll样受体2(TLR2)信号下游的促炎反应增强。我们已经描绘了参与抑制的宿主途径。

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. Mycobacterium tuberculosis is a highly successful human pathogen that has evolved to survive within the host. Our long-term goals are to delineate the mechanisms by which M. tuberculosis interferes with the microbicidal functions of macrophages and evades host immune responses. Understanding the molecular mechanisms underlying M. tuberculosis-host interactions is important for designing therapeutic interventions and vaccine strategies. We have identified Rv2224c, a predicted protease, as being critical for survival in macrophages and in vivo. We hypothesize that Rv2224c is an important virulence factor that proteolytically cleaves M. tuberculosis substrates and modulates the host immune response. While proteases are known to be key virulence factors in other bacterial pathogens, the function of proteases in M. tuberculosis pathogenesis has been largely unexplored. Our preliminary studies indicate that Rv2224c is exported to the cell envelope of mycobacteria. A mutant disrupted in the protease is impaired for growth in macrophages and in vivo. Mice infected with a protease mutant show markedly reduced lung pathology and survive longer than wildtype-infected mice and we have new evidence that Rv2224c modulates host innate immunity. UPDATE 2010 We have demonstrated that Rv2224c suppresses innate immune responses; Rv2224c mutants induce enhanced proinflammatory responses downstream of Toll-like receptor 2 (TLR2)-signaling in macrophages. We have delineated the host pathways that are involved in suppression.