ROLE OF MYCOBACTERIUM TUBERCULOSIS PROTEASE IN PATHOGENESIS AND HOST RESPONSE

结核分枝杆菌蛋白酶在发病机制和宿主反应中的作用

• 批准号: 8357499
• 负责人: Jyothi Rengarajan
• 金额: $ 4.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357499
• 关键词: Cleaved cell; Funding; Genus Mycobacterium; Goals; Grant; Growth; Human; Immune response; Lung; Molecular; Mus; Mycobacterium tuberculosis; National Center for Research Resources; Natural Immunity; Pathogenesis; Pathology; Pathway interactions; Peptide Hydrolases; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Role; Signal Transduction; Source; Therapeutic Intervention; Toll-Like Receptor 2; United States National Institutes of Health; Virulence Factors; cell envelope; cost; design; in vivo; macrophage; microbicide; mutant; pathogen; response; therapeutic vaccine

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 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结核分枝杆菌干扰巨噬细胞的杀菌功能并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。我们已经鉴定出 Rv2224c（一种预测的蛋白酶）对于巨噬细胞和体内的生存至关重要。我们假设 Rv2224c 是一种重要的毒力因子，可通过蛋白水解方式裂解结核分枝杆菌底物并调节宿主免疫反应。虽然已知蛋白酶是其他细菌病原体的关键毒力因子，但蛋白酶在结核分枝杆菌发病机制中的功能很大程度上尚未被探索。我们的初步研究表明，Rv2224c 被输出到分枝杆菌的细胞膜。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明显减少的肺部病理，并且比野生型感染的小鼠存活时间更长，并且我们有新的证据表明 Rv2224c 调节宿主先天免疫。 2010 年更新 我们已经证明 Rv2224c 可以抑制先天免疫反应； Rv2224c 突变体诱导巨噬细胞中 Toll 样受体 2 (TLR2) 信号下游的促炎反应增强。我们已经描述了参与抑制的宿主途径。