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

描述（由申请人提供）：结核病是一种仍然对全球公共卫生构成重大威胁的疾病。在发展中国家，艾滋病毒合并感染的频率以及多重耐药菌株的出现，加剧了这一流行病的严重性。刺激更具保护性的免疫反应的新方法对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在人巨噬细胞反应中的作用，以及这些反应对结核病期间完全免疫反应的影响。本研究拟研究的主要假设是，对IL-27的自分泌反应阻碍了巨噬细胞效应功能和对结核分枝杆菌的有效免疫反应。我们的初步结果表明，当IL-27在il -12处理的巨噬细胞感染期间被中和时，分枝杆菌的恢复显著减少。第一个目的是利用分子方法来验证肿瘤坏死因子和干扰素在这一机制中不可或缺的假设。第二个特定目的是研究IL-12处理和IL-27中和对巨噬细胞效应功能的影响。所涉及的基本原理是，这种治疗产生的干扰素- γ促进了阻碍分枝杆菌生长的毒性细胞内环境。这项工作研究了感染期间一氧化氮参与巨噬细胞反应，并检查了内体途径中分枝杆菌吞噬体的进展。第三个特定目的是验证IL-27 EBI3和p28基因转录控制的新机制。由于IL-27参与宿主对许多慢性感染和疾病状态的反应，包括结核病，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

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.