ROLE OF MYCOBACTERIUM TUBERCULOSIS PROTEASE IN PATHOGENESIS AND HOST RESPONSE

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。次级项目的主要支助 子项目的主要研究者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 表示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。 结核分枝杆菌是一种非常成功的人类病原体，它已经进化到可以在宿主体内生存。我们的长期目标是阐明M。结核病干扰巨噬细胞的杀微生物功能并逃避宿主免疫应答。了解M.结核病与宿主的相互作用对于设计治疗干预措施和疫苗战略十分重要。我们已经鉴定了Rv 2224 c，一种预测的蛋白酶，作为巨噬细胞和体内存活的关键。我们推测Rv 2224 c是一个重要的毒力因子，它通过蛋白水解切割M。结核病基质和调节宿主免疫应答。虽然蛋白酶是已知的其他细菌病原体中的关键毒力因子，但M.结核病的发病机理在很大程度上尚未被探索。我们的初步研究表明，Rv 2224 c输出到分枝杆菌的细胞包膜。蛋白酶中被破坏的突变体在巨噬细胞和体内的生长受到损害。感染蛋白酶突变体的小鼠表现出显著减少的肺部病理学，并且比野生型感染的小鼠存活更长，我们有新的证据表明Rv 2224 c调节宿主先天免疫。 我们已经证明Rv 2224 c抑制先天性免疫反应; Rv 2224 c突变体在巨噬细胞中诱导Toll样受体2（TLR 2）信号传导下游增强的促炎反应。我们已经描述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.