Human Genetic Dissection of Exit from Latency in Tuberculosis

结核病潜伏期退出的人类基因剖析

• 批准号: 8882248
• 负责人: Jean-Laurent Casanova
• 金额: $ 61.93万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8882248
• 关键词: 20 year old; Accounting; Affect; African; Age-Years; Binding; Biological Assay; Biological Markers; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cells; Clinical; Clinical Trials; Collection; Data; Development; Dideoxy Chain Termination DNA Sequencing; Disease; Dissection; Epidemiology; Family; Gene Deletion; Genes; Genetic; Genetic Polymorphism; Genotype; Genus Mycobacterium; HIV; HIV Seropositivity; Haiti; Human; Human Genetics; Immune response; Immune system; Immunity; Impairment; In Vitro; Individual; Intervention; Lymphocyte Subset; Methods; Minority; Molecular; Mus; Mutation; Mycobacterium tuberculosis; Natural Killer Cells; Nuclear; Pathogenesis; Pathway interactions; Patients; Play; Population; Predisposition; Prevention strategy; Pulmonary Tuberculosis; Recruitment Activity; Recurrence; Regulatory T-Lymphocyte; Research; Risk; Role; Sampling; Siblings; Signal Transduction; Study Subject; Subgroup; T cell response; T-Cell Development; T-Lymphocyte; Techniques; Testing; Transgenic Mice; Tuberculosis; Vaccine Research; Variant; base; case control; design; early onset; exome sequencing; genetic linkage analysis; genetic variant; genome wide association study; genome-wide; genome-wide linkage; in vivo; interest; mouse model; novel; novel vaccines; rare variant; transcription factor; tuberculosis immunity

Only a minority of individuals with latent Mycobacterium tuberculosis (Mtb) infection (~5%) develop TB disease, typically pulmonary TB (PTB), due to the reactivation of dormant mycobacteria. There is growing genetic epidemiological evidence that PTB has a strong genetic component in humans, but the molecular basis of susceptibility to Mtb reactivation remains largely unknown. Candidate gene and genome-wide (GW) association studies have suggested that common variants play only a modest role in the genetics of PTB, or that their role is restricted to specific subgroups. We recently showed, by an unbiased GW linkage approach, that common variants of TOX, a gene involved in T-cell and NK-cell development, are associated with PTB in young patients with a short latency duration, in two ethnically different populations. Genetic factors other than TOX may also contribute to PTB, including rare variants of unknown genes. Our project will combine a focused in-depth dissection of the role of TOX in PTB, based on both human and mouse studies, with a GW approach investigating the role of rare variants in PTB. Study subjects will be recruited in Haiti, through the GHESKIO Center, to establish a large case/control sample (HIV-negative and HIV-positive), and a family-based sample with at least two PTB-affected siblings. We will conduct a comprehensive association study of PTB with TOX polymorphisms, and a GW search for rare variants in PTB patients, based on a combination of GW linkage and whole-exome sequencing studies. All variants consistently found to be associated with PTB will be validated immunologically, at the molecular and cellular levels with cutting-edge techniques. We will study the functional impact of previously identified variants located in the 3' region of TOX on T-cell immunity, both in vitro in human cells, and in vivo in mice. Mouse models will be used to investigate the role of TOX in T-cell responses to Mtb infection, together with analyses of endogenous T-cell responses in mice with T cell-specific TOX gene deletion. Our preliminary data indicate that TOX is strongly expressed in human CD4, Treg, NK, and yOT cells and in murine CD4 and Treg cells, and that the 3' end of TOX probably has regulatory activities, -further supporting the candidacy of TOX as a prime regulator of PTB immunity.

只有少数潜伏结核分枝杆菌 (Mtb) 感染的个体 (~5%) 会发展为结核病 由于休眠分枝杆菌重新激活而导致的疾病，通常是肺结核 (PTB)。有不断增长的 遗传流行病学证据表明，PTB 在人类中具有很强的遗传成分，但分子 Mtb 重新激活的易感性基础仍然很大程度上未知。候选基因和全基因组（GW） 关联研究表明，常见变异在 PTB 遗传学中仅发挥很小的作用，或者 他们的作用仅限于特定的子群体。我们最近通过无偏 GW 链接方法表明， TOX（一种参与 T 细胞和 NK 细胞发育的基因）的常见变体与 PTB 相关 在两个不同种族人群中潜伏期较短的年轻患者中。遗传因素 其他 TOX 还可能导致 PTB，包括未知基因的罕见变异。我们的项目将结合 基于人类和小鼠研究，重点深入剖析 TOX 在 PTB 中的作用，并具有 GW 研究罕见变异在 PTB 中的作用的方法。研究对象将通过海地招募 GHESKIO 中心，建立一个大型病例/对照样本（HIV 阴性和 HIV 阳性），以及一个以家庭为基础的 样本中至少有两个受 PTB 影响的兄弟姐妹。我们将进行全面的关联研究 具有 TOX 多态性的 PTB，以及基于组合的 GW 搜索 PTB 患者中的罕见变异 GW连锁和全外显子组测序研究。所有变体一致被发现与 PTB 将通过尖端技术在分子和细胞水平上进行免疫学验证。我们 将研究先前发现的位于 TOX 3' 区域的变异对 T 细胞的功能影响 免疫，包括体外人类细胞和小鼠体内。将使用小鼠模型来研究其作用 TOX 在 T 细胞对 Mtb 感染反应中的作用，以及小鼠内源性 T 细胞反应的分析 T 细胞特异性 TOX 基因缺失。我们的初步数据表明，TOX 在 人类 CD4、Treg、NK 和 yOT 细胞以及鼠 CD4 和 Treg 细胞，并且 TOX 的 3' 末端可能 具有监管活动， -进一步支持 TOX 作为 PTB 免疫主要监管者的候选资格。