Host genetic diversity, mononuclear phagocytes, and outcomes of TB

项目总结 由结核分枝杆菌引起的结核病目前每年导致更多的人死亡。 这一年比包括艾滋病毒在内的任何其他传染病都要多。消除结核病的障碍之一是缺乏 一种足够有效的疫苗。反过来，有效疫苗的开发也因不完整而变得复杂 对结核分枝杆菌保护性免疫相关因素和机制的认识 从对C57BL/6(B6)小鼠的研究中获得的知识。协作型交叉的发展 小鼠，以及初步研究表明CC001和CC002小鼠更能清除结核分枝杆菌 比B6小鼠，提供了更好地了解结核病免疫机制的机会 易操控、经济的实验模型。四个要素为我们提出的方法提供了基础 利用CC001和CC002小鼠更好地了解结核病保护性免疫的机制。它们是：1) 结核分枝杆菌存在于巨噬细胞和其他抗原提呈细胞(统称为单核细胞)中 2)CC001和CC002小鼠对结核分枝杆菌的良好控制 发展适应性(T细胞)免疫；3)CD4T细胞是小鼠对结核病的保护性免疫所必需的， 人；4)CD4T细胞必须与巨噬细胞和其他单核巨噬细胞(MNP)相互作用，以提供 对结核病的保护性免疫。因此，我们提出了一个由两部分组成的工作假说：i)CD4T细胞反应是 CC001和CC002比B6小鼠更有效地对抗结核分枝杆菌；ii)CD4T细胞反应是 由于CC001和CC001中MNP具有优异的抗原提呈和/或抗分枝杆菌活性，因此更有效 CC002，与B6相比，小鼠。为了检验这个由两部分组成的假设，我们将使用既定的和创新的工具 以及对结核分枝杆菌感染的肺部中特定的MNP亚群进行比较研究的方法 CC001、CC002和B6小鼠。我们的研究将包括确定肺中MNP的特定亚群 CC001和CC002小鼠体内杀死结核分枝杆菌的能力更强，以及它们是否更有能力 激活结核分枝杆菌特异性CD4T细胞的能力比B6小鼠的同类细胞要高。我们的研究是 旨在生成关于CC001和CC002小鼠免疫表型的定量数据， 说明了自己对结核分枝杆菌的超强控制，并确定了是否超强的机制(S) 这两个品系的小鼠的免疫力相似或不同。此外，我们的研究旨在提供 量化数据，将有助于在未来研究期间产生的小鼠的表型分析，以绘制和识别 解释CC001和CC002小鼠卓越结核病免疫力的因果遗传变异，最终确定 促进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，他们将致力于宿主导向疗法的开发和 治疗结核病的有效疫苗。

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.