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

结核病是一种严重威胁全球公共卫生的疾病。疫情严重程度 在发展中国家，艾滋病毒合并感染的频率和 多药耐药菌株刺激更具保护性的免疫反应的新方法是 特别关注对抗耐药菌株的增加。我们的长期目标是了解 白细胞介素（IL）-12和IL-27参与人类巨噬细胞反应，以及这些细胞因子对巨噬细胞的影响。 结核病期间的完全免疫反应。待研究的主要假设 在该建议中，对IL-27自分泌/旁分泌反应阻碍巨噬细胞效应子功能， 控制M.结核初步结果表明，当IL-27被中和时， 在IL-12处理的巨噬细胞的感染过程中，分枝杆菌的恢复显著减少。 与分枝杆菌生长的控制相一致的是，干扰素（IFN）-D和TNF-D的产生增加， 感染的巨噬细胞用IL-12和可溶性受体处理以中和IL-27。第一个目标是利用 分子方法来确定重要的细胞因子和测试的假设，肿瘤坏死因子和 IFN-D是这一机制不可或缺的。第二个具体目标是调查IL- 图12显示IL-27对巨噬细胞效应子功能的治疗和中和。所涉及的理由是， 由于这种治疗产生的IFN-D促进了毒性细胞内环境， 分枝杆菌生长。在这个目标中描述的工作调查了一氧化氮在 巨噬细胞的反应，并检查内的分枝杆菌吞噬体的进展 内体途径第三个具体目标检验了一个假设，即新机制的运作， 控制IL-27、EBI 3和p28基因的转录。由于IL-27参与宿主对多种肿瘤的应答， 慢性感染和疾病状态，包括结核病，重要的是要了解分子 调节IL-27基因表达的机制。我们建议对宿主免疫进行基础研究 感染期间的反应，可能对治疗策略和疫苗的设计产生影响。

Tuberculosis is a disease that rennains a nnajor thireat to global public health. The severity of the epidemic has 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 drug 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/paracrine response to IL-27 impedes macrophage effector functions that control growth of M. tuberculosis. Oui- 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. Consistent with control of mycobacterial growth is elevated production of interferon (IFN)-D and TNF-D by infected macrophages treated with IL-12 and a soluble receptor to neutralize IL-27. The first aim utilizes molecular approaches to identify important cytokines and test the hypothesis that tumor necrosis factor and IFN-D 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 IFN-D produced as a result of this treatment promotes a toxic intracellular environment that hinders mycobacterial growth. The work described in this aim investigates the involvement of nitric oxide in the macrophage response during infection and examines progression ofthe 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 implications in design of therapeutic strategies and vaccines.