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.

尽管结核病 (TB) 近 75 年来一直是可以治愈和预防的，但结核病仍然是一个主要的公共疾病 威胁全球健康，是世界上最主要的传染病死因。到 2035 年“消除”结核病的目标 以目前可用的控制策略，在本世纪不太可能实现。开发新 需要治疗和预防工具，例如结核病疫苗，但这种努力受到以下因素的阻碍： 对结核分枝杆菌 (Mtb) 感染的保护机制了解不足。 尽管长期以来人们一直假设宿主遗传在保护中发挥作用，并且基于家族的连锁研究也已证实 尽管结果令人鼓舞，但尚未仔细表征特定基因。迄今为止的研究工作已 由于确定 Mtb 耐药性临床表型的挑战、样本量小以及难以确定 测量结核分枝杆菌的暴露程度。随着高通量微阵列技术的最新进展 然而，测序技术使得大规模的基因研究现在成为可能。在拟议的研究中，我们将 招募 4,000 名最近接触过活动性结核病的家庭接触者作为队列。我们将 识别尽管特征明确、高度暴露于结核病指数但仍未感染的接触者 病例，并将其与感染 Mtb 的家庭接触者进行比较。该研究将在 印度和南非的结核病高发地区。在目标 1 中，我们将表征以下表型 利用结核菌素皮试 (TST) 和干扰素-γ 释放的反应来抵抗 Mtb 感染 对最近暴露于培养确诊的活动性结核病指数病例的队列进行分析（IGRA）。通过整合这些 TST 和 IGRA 结果以及接触者暴露于活动性结核指数病例的严格特征，我们将 能够识别尽管接触程度高但对结核分枝杆菌感染具有抵抗力的个体。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 Mtb 感染具有抵抗力。我们还将调查先前报道的结核病相关的候选 SNP 遗传位点。在目标 3 中，我们将利用新兴的代谢组学领域来确定代谢谱 区分对 Mtb 感染具有抵抗力的个体。鉴定与耐药性相关的代谢簇 将揭示参与抵抗或清除 Mtb 感染的细胞途径，并且还将增强 GWAS 通过提供任何遗传多态性下游效应的功能输出来发现结果。这 公正和综合的方法将为识别基因和途径提供前所未有的机会 参与抵抗结核分枝杆菌感染，并了解结核病背后的多层分子机制 感染。我们的研究团队拥有十多年开展结核病、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。