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.

只有少数患有潜伏分枝杆菌结核病（MTB）感染（〜5％）的人出现结核病 由于休眠分枝杆菌的重新激活，疾病，通常是肺结核（PTB）。有增长 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 对MTB重新激活的敏感性的基础在很大程度上仍然未知。候选基因和全基因组（GW） 关联研究表明，普通变体在PTB的遗传学或 它们的作用仅限于特定的亚组。我们最近通过公正的GW链接方法表明 TOX的常见变体，一种参与T细胞和NK细胞发育的基因，与PTB有关 在延迟持续时间短的年轻患者中，有两个种族不同的人群。遗传因素其他 毒素也可能有助于PTB，包括未知基因的罕见变体。我们的项目将结合一个 基于人类和小鼠研究，重点介绍了毒品在PTB中的作用， 方法研究了稀有变体在PTB中的作用。研究对象将在海地招募 Gheskio中心，建立大型/对照样本（HIV阴性和HIV阳性），以及基于家庭的样本 采样至少两个受PTB影响的兄弟姐妹。我们将对 基于组合 GW连锁和全外观测序研究。所有变体始终发现与 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 将研究位于T-Cell的3'区域中先前鉴定的变体的功能影响 免疫，包括在人类细胞中的体外和小鼠的体内。鼠标模型将用于研究角色 T-Cell对MTB感染的反应中的TOX，以及对小鼠内源性T细胞反应的分析 带有T细胞特异性毒Tox基因缺失。我们的初步数据表明，在 人CD4，Treg，NK和Yot细胞以及在鼠CD4和Treg细胞中，毒物的3'端可能 具有监管活动，以支持TOX作为PTB免疫的主要调节剂的候选人。