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

结核病是一种危害全球公共卫生的疾病。这场流行病的严重性 由于发展中国家与艾滋病毒混合感染的频率以及出现 耐多药菌株。刺激更具保护性的免疫反应的新方法是 特别关注抗药性菌株的增加。我们的长期目标是了解 IL-12和IL-27在人巨噬细胞反应中的作用及其影响 结核病时对完全免疫反应的反应。要调查的主要假说 在这一建议中，IL-27的自分泌/旁分泌反应阻碍了巨噬细胞效应器的功能， 控制结核分枝杆菌生长。OUI-初步结果表明，当IL-27被中和时 在感染经IL-12处理的巨噬细胞期间，分枝杆菌的回收率显著降低。 与控制分枝杆菌生长一致的是，通过增加干扰素(干扰素)-D和肿瘤坏死因子-D的产生 用IL-12和一种中和IL-27的可溶性受体处理感染的巨噬细胞。第一个目标是利用 识别重要细胞因子的分子方法并验证肿瘤坏死因子和 在这一机制中，干扰素-D是不可或缺的。第二个具体目标是调查IL-1的后果-- 12 IL-27对巨噬细胞效应功能的处理和中和作用。其中涉及的理由是 这种治疗产生的干扰素-D促进了有毒的细胞内环境，从而阻碍了 分枝杆菌的生长。在这一目标中描述的工作调查了一氧化氮在 巨噬细胞在感染过程中的反应，并检查体内分枝杆菌吞噬小体的进展 内体途径。第三个具体目标是检验这样一种假设，即新机制的作用是 控制IL-27、EBI3和p28基因转录。由于IL-27参与了宿主对许多 慢性感染和疾病状态，包括结核病，重要的是了解分子 调节IL-27基因表达的机制。我们提出了对宿主免疫的基础研究 感染期间的反应可能对治疗策略和疫苗的设计有影响。

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.