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

• 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
• 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; 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

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.

项目摘要 由细菌，结核分枝杆菌引起的结核病（TB）目前杀死更多人类 年份比包括艾滋病毒在内的任何其他传染病。消除结核病的障碍之一是缺乏 足够有效的疫苗。反过 了解保护性免疫与结核分枝杆菌的相关性和机制以及有限的 从C57BL/6（B6）小鼠的研究中获得的知识。协作十字架的发展 小鼠以及最初的研究表明CC001和CC002小鼠更能清除结核分枝杆菌。 比B6小鼠比B6小鼠更好地了解高度了解TB的免疫机制 可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小鼠更好地了解对结核病保护性免疫的机制。他们是：1） 结核分枝杆菌驻留在巨噬细胞和其他抗原呈递细胞中（统称为单核 肺中的吞噬细胞）； 2）在CC001和CC002小鼠中的结核分枝杆菌的出色控制之后 适应性（T细胞）免疫的发展； 3）CD4 T细胞对于对小鼠的TB保护至关重要，并且 人类4）CD4 T细胞必须与巨噬细胞和其他单核吞噬细胞（MNP）相互作用才能提供 对结核病的保护性免疫。因此，我们提出了一个分为两部分的工作假设：i）CD4 T细胞反应是 在CC001和CC002中，对结核分枝杆菌的有效性比B6小鼠更有效。 ii）CD4 T细胞反应是 由于CC001中MNP的出色抗原呈递和/或抗菌活性，因此更有效 CC002，与B6小鼠相比。为了检验这两个部分的假设，我们将使用已建立的创新工具 和在结核分枝杆菌感染的肺中对MNP的特定子集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的特定子集是否 CC001和CC002小鼠的体内能力更有能力杀死结核分枝杆菌，并且它们是否更有能力 与B6小鼠相比，激活结核分枝杆菌特异性CD4 T细胞的含量是其对应物。我们的研究是 旨在生成有关CC001和CC002小鼠免疫表型的定量数据 解释了他们对结核分枝杆菌的优越控制，并确定上级的机制是否 两种小鼠菌株的免疫力相似或不同。此外，我们的研究旨在提供 定量数据将促进未来研究期间产生的小鼠的表型，以绘制和识别 造成CC001和CC002小鼠中最高结核病的因果遗传变异，以最终定义 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 对于人类的翻译研究，它们将与宿主定向疗法的发展和 有效的结核病疫苗。