Host genetic diversity, mononuclear phagocytes, and outcomes of TB

项目摘要 由结核分枝杆菌引起的结核病（TB），目前每年杀死更多的人。 比任何其他传染病，包括艾滋病毒。消除结核病的障碍之一是缺乏 有效的疫苗反过来，有效疫苗的开发由于不完全的免疫系统而变得复杂。 了解对M的保护性免疫的相关因素和机制。结核病和有限的 从C57 BL/6（B6）小鼠研究中获得的知识。协作交叉的发展 小鼠，以及初步研究表明，CC 001和CC 002小鼠更能够清除M。结核 比B6小鼠，提供了更好地了解结核病免疫机制的机会， 易操作和经济的实验模型。四个要素为我们提出的方法提供了基础， 使用CC 001和CC 002小鼠更好地理解对TB的保护性免疫的机制。它们是：1） M.结核病存在于巨噬细胞和其他抗原呈递细胞（统称为单核细胞 吞噬细胞）; 2）M.观察CC 001和CC 002小鼠中的结核病， 适应性（T细胞）免疫的发展; 3）CD 4 T细胞对于小鼠对TB的保护性免疫是必需的， 人; 4）CD 4 T细胞必须与巨噬细胞和其他单核吞噬细胞（MNP）相互作用， 对肺结核的保护性免疫因此，我们提出了一个两部分的工作假设：i）CD 4 T细胞反应是 对M更有效。在CC 001和CC 002小鼠中，与B6小鼠相比，结核病小鼠中的CD 4 T细胞应答更高;以及ii）CD 4 T细胞应答更低， 由于MNP在CC 001中的上级抗原呈递和/或抗分枝杆菌活性而更有效， CC 002小鼠与B6小鼠比较。为了验证这两部分假设，我们将使用现有的和创新的工具 和方法进行比较研究的特定子集的MNP在肺的M。结核病感染者 CC 001、CC 002和B6小鼠。我们的研究将包括确定是否特定亚群的MNP在肺部 CC 001和CC 002小鼠对M.以及它们是否更有能力 激活M。结核病特异性CD 4 T细胞比它们在B6小鼠中的对应物多。我们的研究是 设计用于生成CC 001和CC 002小鼠免疫表型的定量数据， 他们对M的控制力上级。结核病，并确定是否机制的上级 这两种小鼠的免疫力是相似的或不同的。此外，我们的研究旨在提供 定量数据，这将有助于在未来的研究中产生的小鼠表型，以绘制和识别 在CC 001和CC 002小鼠中解释上级TB免疫力的致病遗传变异，以最终确定 有助于结核病免疫的分子机制。我们预计我们的发现将为 用于人类的翻译研究，它们将有助于开发宿主导向疗法， 有效的结核病疫苗。

PROJECT SUMMARY Tuberculosis (TB), caused by the bacterium, Mycobacterium tuberculosis, currently kills more humans every year than does any other infectious disease, including HIV. Among the obstacles to eliminating TB is the lack of a sufficiently-efficacious vaccine. In turn, development of efficacious vaccines is complicated by incomplete understanding of the correlates and mechanisms of protective immunity to M. tuberculosis and by the limited knowledge that has been gained from studies in C57BL/6 (B6) mice. The development of Collaborative Cross mice, together with initial studies that reveal that CC001 and CC002 mice are more able to clear M. tuberculosis than are B6 mice, provides the opportunity to better understand the mechanisms of immunity to TB in a highly tractable and economical experimental model. Four elements provide the basis for our proposed approach to using CC001 and CC002 mice to better understand the mechanisms of protective immunity to TB. They are: 1) M. tuberculosis resides in macrophages and other antigen-presenting cells (collectively termed mononuclear phagocytes) in the lungs; 2) the superior control of M. tuberculosis in CC001 and CC002 mice is observed after development of adaptive (T cell) immunity; 3) CD4 T cells are essential for protective immunity to TB in mice and humans; 4) CD4 T cells must interact with macrophages and other mononuclear phagocytes (MNP) to provide protective immunity to TB. Therefore, we propose a two-part working hypothesis: i) CD4 T cell responses are more effective against M. tuberculosis in CC001 and CC002 than in B6 mice; and ii) CD4 T cell responses are more effective due to superior antigen-presenting and/or antimycobacterial activities of MNP in CC001 and CC002, compared with B6, mice. To test that two-part hypothesis, we will use established and innovative tools and methods to perform comparative studies of specific subsets of MNP in the lungs of M. tuberculosis-infected CC001, CC002, and B6 mice. Our studies will include determining whether specific subsets of MNP in the lungs of CC001 and CC002 mice are more capable of killing M. tuberculosis in vivo and whether they are more capable of activating M. tuberculosis-specific CD4 T cells than are their counterparts in B6 mice. Our studies are designed to generate quantitative data on the immunological phenotypes of CC001 and CC002 mice that account for their superior control of M. tuberculosis, and to determine whether the mechanism(s) of superior immunity in the two strains of mice are similar or are distinct. Furthermore, our studies are designed to provide quantitative data that will facilitate phenotyping of mice generated during future studies to map and identify the causal genetic variants that account for superior TB immunity in CC001 and CC002 mice, to ultimately define molecular mechanisms that contribute to TB immunity. We anticipate that our discoveries will provide a basis for translational studies in humans, and that they will contibute to development of host-directed therapies and efficacious vaccines for TB.