Host genetic diversity, mononuclear phagocytes, and outcomes of TB

宿主遗传多样性、单核吞噬细胞和结核病的结果

基本信息

批准号：
10005738
负责人：
Joel D. Ernst
金额：
$ 28.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-16 至 2022-05-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005738
关键词：
Aerosols Alveolar Macrophages Antigen-Presenting Cells Antigens Antimycobacterial Agents Bacteria Budgets CD4 Positive T Lymphocytes Cells Characteristics Chromosome Mapping Colony-forming units Communicable Diseases Comparative Study Data Dendritic Cells Development Elements Experimental Models Foundations Future Genetic Genetic Variation Goals Growth HIV Human Immune response Immunity Immunologics Infection Intervention Kinetics Knowledge Lung Maps Mediator of activation protein Methods Molecular Mononuclear Mouse Strains Mus Mycobacterium tuberculosis Mycobacterium tuberculosis H37Rv Outcome Pathogenesis Phagocytes Pharmacology Phase Phenotype Plasmids Population Property Public Health Publishing Reporter Reporting Research T cell response T-Lymphocyte Testing Time Tuberculosis Tuberculosis Vaccines Vaccines adaptive immune response adaptive immunity design effector T cell experimental study genetic variant in vivo innovation macrophage recruit spatial relationship tool translational study tuberculosis immunity tuberculosis treatment vaccine development

项目摘要

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.

项目概要结核病 (TB) 由结核分枝杆菌引起，目前每年导致更多人死亡年的发病率比任何其他传染病（包括艾滋病毒）都要高。消除结核病的障碍之一是缺乏足够有效的疫苗。反过来，有效疫苗的开发因不完整而变得复杂。了解结核分枝杆菌保护性免疫的相关性和机制以及有限的从 C57BL/6 (B6) 小鼠研究中获得的知识。协同交叉的发展小鼠，以及初步研究表明 CC001 和 CC002 小鼠更能够清除结核分枝杆菌与 B6 小鼠相比，提供了更好地了解高度结核病免疫机制的机会易于处理且经济的实验模型。四个要素为我们提出的方法提供了基础使用 CC001 和 CC002 小鼠更好地了解结核病的保护性免疫机制。它们是：1）结核分枝杆菌存在于巨噬细胞和其他抗原呈递细胞（统称为单核细胞）中。吞噬细胞）在肺部； 2)在CC001和CC002小鼠中观察到对结核分枝杆菌的优越控制适应性（T 细胞）免疫的发展； 3) CD4 T细胞对于小鼠对结核病的保护性免疫至关重要人类； 4）CD4 T细胞必须与巨噬细胞和其他单核吞噬细胞（MNP）相互作用以提供对结核病的保护性免疫力。因此，我们提出了一个由两部分组成的工作假设：i) CD4 T 细胞反应是 CC001 和 CC002 小鼠比 B6 小鼠更能有效对抗结核分枝杆菌； ii) CD4 T 细胞反应是由于 CC001 和 MNP 具有优异的抗原呈递和/或抗分枝杆菌活性，因此更加有效 CC002，与 B6，小鼠相比。为了检验这个由两部分组成的假设，我们将使用成熟的和创新的工具对结核分枝杆菌感染者肺部特定 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部中 MNP 的特定亚群是否 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与 B6 小鼠中的对应物相比，激活结核分枝杆菌特异性 CD4 T 细胞的能力更强。我们的研究是旨在生成 CC001 和 CC002 小鼠免疫表型的定量数据解释他们对结核分枝杆菌的优越控制，并确定优越的机制是否两种小鼠品系的免疫力相似或不同。此外，我们的研究旨在提供定量数据将有助于在未来的研究中生成小鼠表型，以绘制和识别导致 CC001 和 CC002 小鼠具有优异结核病免疫力的因果遗传变异，最终定义有助于结核病免疫的分子机制。我们预计我们的发现将提供基础用于人类转化研究，并且它们将有助于开发针对宿主的疗法和有效的结核病疫苗。