Identify the host genetic determinants of immune response and TB countrol

确定免疫反应和结核病控制的宿主遗传决定因素

• 批准号: 10089387
• 负责人: MEGAN B MURRAY
• 金额: $ 57.92万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089387
• 关键词: Acute; Adjuvant; Animal Model; Antigen Presentation; Antigens; Bypass; Cavia; Cell physiology; Classification; Clinical; Data; Development; Disease; Disease Progression; Formulation; Gene Expression Profiling; Genes; Genetic; Genetic Determinism; Household; Human; Immune; Immune response; Immunodiagnostics; Immunological Diagnosis; Immunologics; Immunotherapy; Individual; Infection; Lipids; MHC antigen; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Metabolic; Methods; Molecular; Mucous Membrane; Outcome; Patients; Peptide/MHC Complex; Persons; Peru; Play; Population; Population Study; Proteins; Protocols documentation; Relapse; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Sorting - Cell Movement; Specificity; System; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transcript; Translational Research; Tuberculosis; Vaccine Design; Vitamins; cohort; comparative; exome; gene product; genetic variant; in vivo Model; infection risk; innovation; mycobacterial; nano-string; new technology; protein activation; protein expression; technology development; translational study; vaccine development

T cells play a critical role in the host response to Mtb infection, and are their antigen specificity forms the basis of widely used clinical immunodiagnostic tests. MHC-restricted effector memory T cells protect the host from progression to active TB disease, but the particular effector functions, which mediate control are unknown. In a well characterized human patient cohort in Lima, Peru, we will determine the association of active TB disease with 400 transcripts measured in highly purified effector memory T cells. Transcripts associated with lack of disease progression will be validated by PCR and protein measurements to define gene products that can be measured as surrogates for protection from TB progression and targets for immunotherapy development. Nearly all current technology development efforts related to adjuvant formulation, vaccine design and immunodiagnosis focus on MHC antigen presenting molecules. However, recent studies show that non-classical CDIb and MRI proteins present mycobacterial lipids and metabolites to T cells in TB disease. Emphasizing new ex vivo methods and CD1 tetramers, we will measure the relationship of expansion of lipid- and metabolite-specific GEM T cells and MAIT cells during human and guinea pig infection and relapse. In particular, we propose to (a) measure GEM T cell expansion ex vivo during acute human tuberculosis infection (b) comparative nanostring profiling of effector functions of MAIT cells and GEM T cells, and (c) detect CDIb-restricted T cells in guinea pigs using CDIb tetramers. These translational studies seek to establish the first tractable small animal model of in vivo CDIb function and detect a causal relationship of infection with invariant T cell activation. Bypassing the genetic complexities of human MHC proteins, activation of invariant T cells by lipids and metabolites offers potentially more uniform outcomes that could be detected or modulated with lipids and vitamin metabolites (Project 4).

T细胞在宿主对Mtb感染的应答中起着关键作用，并且它们的抗原特异性形成免疫应答。 广泛使用的临床免疫诊断测试的基础。MHC限制性效应记忆T细胞保护宿主 从进展到活动性结核病，但特定的效应功能，介导控制， 未知在秘鲁利马的一个充分表征的人类患者队列中，我们将确定 活动性TB疾病，在高度纯化的效应记忆T细胞中测量了400个转录物。成绩单 将通过PCR和蛋白质测量来验证与缺乏疾病进展相关的，以确定 基因产物可以作为保护免受TB进展的替代物和 免疫疗法的发展。目前几乎所有的技术开发工作都与佐剂有关。 疫苗的制备、疫苗设计和免疫诊断都集中在MHC抗原呈递分子上。然而，在这方面， 最近的研究表明，非经典的CDIb和MRI蛋白呈现分枝杆菌脂质和代谢产物， to T细胞in TB结核病.强调新的离体方法和CD1四聚体，我们将测量 在人类和哺乳动物中脂质和代谢物特异性GEM T细胞和MAIT细胞扩增的关系 豚鼠感染和复发。特别地，我们提出（a）离体测量GEM T细胞扩增， 在急性人结核病感染期间（B）MAIT的效应子功能的比较性纳米串分析 细胞和GEM T细胞，和（c）使用CDIb四聚体检测豚鼠中的CDIb限制性T细胞。这些 转化研究寻求建立体内CDIb功能的第一个易处理的小动物模型， 检测感染与不变T细胞活化的因果关系。分析遗传复杂性， 人类MHC蛋白，通过脂质和代谢物激活不变的T细胞，提供了潜在的更均匀的 可以检测或调节脂质和维生素代谢产物的结果（项目4）。