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

虽然结核病（TB）已经可以治愈和预防了近75年，但结核病仍然是一个主要的公共疾病。 健康威胁全球，作为世界领先的传染病死亡原因。到2035年“消除”结核病的目标 在本世纪用目前可用的控制策略是不可能实现的。开发新 治疗和预防工具，如结核病疫苗，是必要的，但这种努力受到阻碍， 对结核分枝杆菌（Mtb）感染的保护机制认识不足。 尽管宿主遗传在保护中的作用早已被假定，并且基于家族的连锁研究已经证实了这一点， 尽管结果令人鼓舞，但还没有仔细鉴定出特定的基因。迄今为止的研究工作 由于在确定Mtb耐药的临床表型方面的挑战、小样本量和难以确定Mtb耐药的临床表型， 测量暴露于Mtb的程度。随着高通量微阵列和 然而，随着测序技术的发展，大规模的基因研究现在已经成为可能。在拟议的研究中，我们将 招募4，000名最近暴露于活动性结核病的家庭接触者。我们将 确定接触者中未感染的人，尽管他们已被明确描述，高度暴露于结核病指数 例，并与家庭接触者谁成为结核病感染。该研究将于 印度和南非的结核病高发区。在目标1中，我们将描述以下表型： 使用对结核菌素皮肤试验（TST）和干扰素-γ释放的反应来抵抗Mtb感染 在最近暴露于经培养确认的活动性TB指标病例的队列中进行IGRA检测。通过整合这些 TST和IGRA结果与接触者暴露于活动性结核指标病例的严格特征，我们将 能够识别尽管高度暴露但仍抵抗Mtb感染的个体。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 对结核杆菌感染有抵抗力。我们还将研究先前报道的结核病相关基因中的候选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感染有抵抗力的个体。与耐药性相关的代谢簇的鉴定 将揭示参与抵抗或清除Mtb感染的细胞途径， 通过提供任何遗传多态性的下游效应的功能输出来分析结果。这 公正和综合的方法将提供前所未有的机会，以确定基因和途径 参与抵抗结核分枝杆菌感染，并了解结核病的多层分子机制 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，这将使我们能够实现这项研究的创新科学目标。

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.