The involvement of IL-12 and IL-27 in immunity to Mycobacterium tuberculosis

描述（由申请人提供）：结核病是一种仍然是全球公共卫生的主要威胁的疾病。发展中国家艾滋病毒合并感染的频率和多重耐药菌株的出现加剧了艾滋病的严重性。刺激更具保护性的免疫反应的新方法对于对抗多药耐药菌株的增加特别感兴趣。我们的长期目标是了解白细胞介素（IL）-12和IL-27在人类巨噬细胞反应中的参与，以及这些反应对结核病期间完整免疫反应的影响。本研究的主要假设是，对IL-27的自分泌反应阻碍了巨噬细胞效应功能和对M.结核我们的初步结果表明，当IL-27在IL-12处理的巨噬细胞感染过程中被中和时，分枝杆菌的恢复显著减少。第一个目的是利用分子方法来测试肿瘤坏死因子和干扰素-γ是这一机制不可或缺的假设。第二个具体目的是研究IL-12处理和IL-27中和对巨噬细胞效应子功能的影响。所涉及的基本原理是，这种治疗产生的干扰素-γ促进了有毒的细胞内环境，阻碍了分枝杆菌的生长。所描述的工作调查了一氧化氮在感染过程中参与巨噬细胞反应，并检查了内体途径内分枝杆菌吞噬体的进展。第三个具体目标是检验新机制控制IL-27、EBI 3和p28基因转录的假设。由于IL-27参与宿主对许多慢性感染和疾病状态（包括结核病）的反应，因此了解调节IL-27基因表达的分子机制非常重要。我们提出了基本的 研究感染过程中的宿主免疫反应，这可能对设计免疫策略具有重要意义，可能会促进耐多药结核病的治疗和疫苗开发。

DESCRIPTION(provided by applicant): Tuberculosis is a disease that remains a major threat to global public health. The severity of the epidemichas been intensified by the frequency of coinfection with HIV in developing nations and the emergence of multidrug resistant strains. Novel approaches to stimulate a more protective immune response are of particular interest to combat the increase in multidrug resistant strains. Our long-term objective is to understand the involvement of interleukin (IL)-12 and IL-27 in human macrophage responses and the impact of these responses on the complete immune response during tuberculosis. The major hypothesis to be investigated in this proposal is that autocrine response to IL-27 impedes macrophage effector functions and effective immune responses to M. tuberculosis. Our preliminary results have indicated that when IL-27 is neutralized during infection of IL-12-treated macrophages, there is a significant reduction in mycobacterial recovery. The first aim utilizes molecular approaches to test the hypothesis that tumor necrosis factor and interferon-gamma are indispensable to this mechanism. The second specific aim investigates the consequences of IL-12 treatment and neutralization of IL-27 on macrophage effector functions. The rationale involved is that interferon-gamma produced as a result of this treatment promotes a toxic intracellular environment that hinders mycobacterial growth. The work described investigates the involvement of nitric oxide in the macrophage response during infection and examines progression of the mycobacterial phagosome within the endosomal pathway. The third specific aim tests the hypothesis that novel mechanisms operate to control transcription of IL-27 EBI3 and p28 genes. Since IL-27 is involved in host responses to a number of chronic infections and disease states, including tuberculosis, it is important to understand the molecular mechanisms that regulate IL-27 gene expression. We have proposed basic research into host immune responses during infection that could have important implications in design of immunotherapeutic strategies that may advance treatment of multidrug resistant tuberculosis and vaccine development.