Characterization of Genomics and Metabolomics among Individuals Highly-Exposed, but resistant to Mtb Infection

高度暴露但对 Mtb 感染具有抵抗力的个体的基因组学和代谢组学特征

• 批准号: 10208663
• 负责人: Neel Rajnikant Gandhi
• 金额: $ 77.52万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208663
• 关键词: Biological; Biological Assay; CCDC6 gene; Cause of Death; Cells; Cessation of life; Collection; Communicable Diseases; Data; Development; Diagnosis; Disease; Enrollment; Environmental Risk Factor; Exposure to; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic study; Genomics; Goals; HIV; Hepatitis C; Household; Human; Incidence; India; Individual; Infection; Integration Host Factors; Interferon Type II; Intervention; Leprosy; Measures; Mediating; Metabolic; Mycobacterium tuberculosis; Output; Pathogenesis; Pathway interactions; Patients; Phenotype; Pilot Projects; Play; Population; Predisposition; Prevention; Prevention strategy; Public Health; Pulmonary Tuberculosis; Reporting; Research; Resistance; Resolution; Role; Sample Size; South Africa; Structure of molecular layer of cerebellar cortex; Technology; Test Result; Tuberculin Test; Tuberculosis; Tuberculosis Vaccines; United States National Institutes of Health; Vaccines; Variant; acquired factor; adaptive immune response; clinical phenotype; cohort; experience; genetic linkage analysis; genetic predictors; genetic risk factor; genetic variant; genome wide association study; genomic locus; indexing; innovation; liquid chromatography mass spectrometry; metabolic profile; metabolome; metabolomics; multidisciplinary; novel therapeutics; novel vaccines; prevent; resistance mechanism; response; small molecule; tool

Although tuberculosis (TB) has been curable and preventable for nearly 75 years, TB remains a major public health threat globally, as the world’s leading infectious disease cause of death. Goals to “eliminate” TB by 2035 are unlikely to be achieved in this century with the currently available control strategies. Development of new therapeutic and prevention tools, such as a TB vaccine, is needed, but such efforts are hampered by insufficient understanding of the mechanisms of protection against Mycobacterium tuberculosis (Mtb) infection. Although a host genetic role in protection has long been postulated and family-based linkage studies have had promising results, no specific genes have yet been carefully characterized. Research efforts to date have been limited by challenges in defining clinical phenotypes of Mtb resistance, small sample sizes, and difficulty in measuring the degree of exposure to Mtb. With recent advances in high-throughput micro-array and sequencing technology, however, large-scale genetic studies are now possible. In the proposed study, we will enroll a cohort of 4,000 household contacts who have been recently exposed to active TB disease. We will identify contacts who remain uninfected, despite a well-characterized, high degree of exposure to a TB index case, and compare them with household contacts who become infected with Mtb. The study will take place in the high TB incidence settings of India and South Africa. In Aim 1, we will characterize a phenotype for resistance to Mtb infection using responses to both tuberculin skin test (TST) and interferon-gamma release assays (IGRA) in a cohort recently exposed to a culture-confirmed active TB index case. By integrating these TST and IGRA results with rigorous characterization of contacts’ exposure to active TB index cases, we will be able to identify individuals who have resisted Mtb infection despite a high degree of exposure. In Aim 2, we will conduct a genome-wide association study (GWAS) to identify common and rare genetic variants associated with resistance to Mtb infection. We will also investigate the candidate SNPs in previously reported TB-related genetic loci. In Aim 3, we will leverage the emerging field of metabolomics to identify metabolic profiles that distinguish individuals resistant to Mtb infection. Identification of metabolic clusters associated with resistance will reveal cellular pathways involved in resisting or clearing Mtb infection, and will also enhance the GWAS findings by providing a functional output of the downstream effects of any genetic polymorphisms. This unbiased and integrated approach will provide an unprecedented opportunity to identify genes and pathways involved in resistance to Mtb infection, and understand the multi-layered molecular mechanisms underlying TB infection. Our research team has more than a decade of experience conducting TB, household contact, genomics and metabolomics studies that will allow us to achieve the innovative scientific aims of this study.

尽管近75年来结核病一直是可治愈和可预防的，但结核病仍然是一个主要的公共疾病。 全球健康威胁，成为世界主要的传染病死亡原因。到2035年“消灭”结核病的目标 以目前可用的控制策略，这些都不太可能在本世纪实现。新技术的发展 需要治疗和预防工具，如结核病疫苗，但这种努力受到以下因素的阻碍 对结核分枝杆菌(Mtb)感染的保护机制认识不足。 尽管寄主基因在保护中的作用长期以来一直被假设，而且基于家庭的连锁研究已经有了 尽管结果令人振奋，但目前还没有具体的基因被仔细描述。到目前为止，研究工作一直在进行 受限于确定结核分枝杆菌耐药临床表型的挑战，样本量小，以及 测量接触结核杆菌的程度。随着高通量微阵列和 然而，测序技术，大规模的基因研究现在是可能的。在建议的研究中，我们会 纳入最近接触活动性结核病的4000名家庭接触者的队列。我们会 确定未感染的接触者，尽管具有良好的特征，接触结核病指数的程度很高 病例，并与感染结核分枝杆菌的家庭接触者进行比较。研究将在#年进行。 印度和南非的结核病高发环境。在目标1中，我们将描述一种表型 通过对结核菌素皮肤试验(TST)和干扰素-γ释放的反应来抵抗结核分枝杆菌感染 最近暴露于培养确认的活动性结核病指数病例的队列中的检测(IGRA)。通过集成这些 TST和IGRA结果与接触者接触活动性结核病指数病例的严格特征，我们将 能够识别尽管高度暴露但仍抵抗结核分枝杆菌感染的个人。在目标2中，我们将 进行全基因组关联研究(GWAS)以确定相关的常见和罕见遗传变异 对结核分枝杆菌感染具有抵抗力。我们还将调查以前报告的与结核病相关的候选SNP 遗传基因。在目标3中，我们将利用新陈代谢组学的新兴领域来确定 区分对结核分枝杆菌感染耐药的个体。鉴定与抗药性相关的代谢簇 将揭示参与抵抗或清除结核分枝杆菌感染的细胞途径，并将增强GWAs 通过提供任何遗传多态的下游效应的功能输出来发现。这 不偏不倚的综合方法将为识别基因和途径提供前所未有的机会 参与对结核分枝杆菌感染的抵抗，并了解结核病背后的多层分子机制 感染。我们的研究团队有十多年的结核病、家庭接触、 基因组学和代谢组学研究将使我们能够实现这项研究的创新科学目标。