Multidimensional Analysis of Immune Status of Latent M. Tuberculosis Infection

摘要/摘要 活动性结核病(TB)是人类死亡和疾病的主要原因。它也是最常见的致命疾病 全世界艾滋病毒/艾滋病的机会性感染。目前的新生儿卡介苗并没有提供值得注意的 预防成人肺结核病，并且没有候选疫苗在委员会和/或 对感染或疾病提供可靠的保护。过去的研究已经确定了特定的免疫反应 与保护相关的。但就像大多数疫苗策略中使用的那样，简单地增强这些反应就是 不足以提供保护。最近的实验表明，持久性分枝杆菌处于活跃状态 潜伏感染是通过主动免疫反应来维持的。更好地了解如何 潜伏的结核病由免疫系统控制，对于开发可能打开的治疗假说是必不可少的 临床干预的新途径。 除了转录分析，大多数对结核分枝杆菌反应的研究包括有针对性的分析和重点 无论是儿童还是成年人群，都表现出高发病率。为了更好地了解潜伏性结核病 受控，我们创造了一个独特而强大的研究设计。首先，我们将使用最近开发的 技术，包括质量细胞术(CyTOF)和RNAseq，以实现广泛、公正和高通量 分析。我们将把这些强大的新技术应用于从13-16岁的患者身上收集的材料 很多年了。这一年龄段将儿童和成人分成不同的年龄段，被认为是结核病的“黄金时代” 死亡率和流动性都很低。有了这个青少年群体，我们希望降低潜伏期固有的复杂性， 从接近灭菌免疫的疾病到亚临床活动性疾病，都有可能发生。此外，我们还将 利用生物信息学工具整合和推断建议的两种细胞和转录组图谱 目标1和目标2。此外，我们将使用一种新的集成计算分析来比较我们的结果 与公共数据库中的其他结核病研究一起发表在AIM 3中。我们的目标是对结核病程如何有新的认识 与成人和儿童相比，青少年的感染得到了控制，并确定了 调解和/或预测从潜伏感染到活动性疾病的转变。

Summary/Abstract Active tuberculosis (TB) is a major cause of human death and disease. It is also the most common fatal opportunistic infection in HIV/AIDS worldwide. The current neonatal BCG vaccine does not provide notable protection against adult pulmonary TB and none of the vaccine candidates show efficacy in board and/or reliable protection against either infection or disease. Past studies have identified specific immune responses associated with protection. But simply boosting these responses as employed in most vaccine strategies was not sufficient to provide protection. Recent experiments indicate that persistent mycobacteria are in an active state, and that latent infection is maintained though an active immune response. A better understanding of how latent TB is controlled by the immune system is essential for developing therapeutic hypothesis that could open new avenues for clinical intervention. Other than transcriptional analysis, most studies of Mtb responses consist of targeted assays and a focus on either children or adult populations that show high disease rates. To better understand how latent TB is controlled, we have created a unique and powerful study design. First, we will use recently developed technologies, including mass cytometry (CyTOF) and RNAseq for broad, unbiased and high-throughput analyses. We will apply these powerful new techniques to a material collected from patients between 13-16 years old. This age group stratifies children and adults and is noted to be the “golden age” in TB where mortality and mobility is low. With this adolescent cohort, we hope to reduce the complexity inherent to latency, which can vary from something close to sterilizing immunity to subclinical active disease. In addition, we will employ bioinformatics tools to integrate and infer across two the cellular and transcriptome profiling proposed in Aim 1 and 2. Furthermore, we will use a novel integrated computationally analyses to compare our results with other TB studies from public database in Aim 3. Our goal is to gain new insight into how the course of Mtb infection is controlled in adolescents as compared with that from adults and children, and to identify factors that mediate and/or predict transitions from latent infection to active disease.