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

描述(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。发展中国家与艾滋病毒混合感染的频率和多重耐药菌株的出现加剧了疫情的严重性。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有意义。我们的长期目标是了解IL-12和IL-27在人类巨噬细胞反应中的作用，以及这些反应在结核病期间对完全免疫反应的影响。在这项建议中要研究的主要假设是，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在感染经IL-12处理的巨噬细胞期间被中和时，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-γ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治疗和IL-27中和对巨噬细胞效应功能的影响。其基本原理是，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期间巨噬细胞反应中的参与，并检查了分枝杆菌吞噬小体在内体途径中的进展。第三个特定目的是检验新机制控制IL-27、EBI3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的反应，包括结核病，了解调节IL-27基因表达的分子机制是很重要的。我们已经提出了基本的 对感染期间宿主免疫反应的研究可能对设计免疫治疗策略具有重要意义，这些策略可能会促进耐多药结核病的治疗和疫苗的开发。

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.