Pathway analysis of tuberculosis pathogenesis

描述(申请人提供)：结核病(TB)，由结核分枝杆菌(Mtb)引起，是一个重大的全球公共卫生问题，特别是在撒哈拉以南非洲，那里的结核病流行率随着艾滋病毒大流行的上升而急剧增加。以前的研究提供了强有力的证据表明宿主遗传因素有助于结核病的风险；这些研究确定了潜在的候选基因，但尚未出现关于结核病遗传易感性的共识模型，也没有研究考察遗传对结核分枝杆菌感染早期阶段的影响。目前的建议利用患者和通过结核病研究单位(TBRU)NIH合同收集的数据。自1995年以来，我们一直在乌干达进行一项家庭接触研究，在那里我们能够观察慢性结核分枝杆菌感染和活动性结核病的遗传和环境风险因素。我们之前的工作主要集中在遗传对免疫反应的影响以及结核分枝杆菌感染的自然病程。我们已经证明，TNFR1、IL10和IFNGR1基因与结核病有关，但与结核分枝杆菌感染的耐药性无关。我们最近完成了基因组扫描，发现了与Mtb抗性相关的新的染色体区域2q21-2q24和5p13-5q22。我们还确定了与结核病进展相关的先天免疫反应变量，但尚未评估与结核分支杆菌感染抵抗力相关的免疫因素。我们的初步结果表明，与结核分枝杆菌感染抗性和结核病发展相关的遗传和免疫因素不同。此外，我们假设宿主基因、先天免疫反应和流行病学因素之间的复杂相互关系共同影响结核分枝杆菌感染和发展为结核病。为了充分研究这个由基因和免疫因子组成的复杂网络，我们建议构建一个全面的途径模型。为此，我们提出了三个目标。首先，我们建议对这些新的染色体区域进行精细定位，并分析关键免疫途径中的候选基因，以确定与结核分枝杆菌感染抗性相关的基因。其次，我们建议分析一些细胞因子对天然免疫配基的反应，以确定与抵抗结核分枝杆菌感染相关的天然免疫反应的各个方面。第三，我们开发了一个适用于家庭数据分析的结构方程建模框架，并建议使用该模型分析这些数据并公开软件。我们将在长期的家庭接触研究中分析对结核分枝杆菌感染耐药的遗传和免疫学预测因素。这也将提供对结核分枝杆菌感染抵抗力的第一次检查；由于我们彻底的研究设计，我们独特地准备分析这种新的表型。公共卫生相关性：结核病(TB)是一种对公共卫生具有重大意义的疾病，全世界有三分之一的人感染了结核分枝杆菌(Mtb)，每年新增近800万结核病病例，每年有200万人死于结核病。以前的研究表明，易从结核杆菌感染发展为活动性结核病的遗传和免疫因素都起到了作用，但这些因素没有同时进行分析，也没有确定与“健康”未感染状态相关的因素。该项目的发现将扩大对结核分枝杆菌感染和结核病的遗传、流行病学和免疫学联合影响的知识，这将有助于改进疫苗和治疗方法的开发。

DESCRIPTION (provided by applicant): Tuberculosis (TB), caused by M. tuberculosis (Mtb), is a significant, global public health problem, particularly in sub-Saharan Africa, where the prevalence of TB is increasing dramatically with the rise of the HIV pandemic. Previous studies provide strong evidence that host genetic factors contribute to the risk for TB disease; those studies identified potential candidate genes, but no consensus model for the genetic susceptibility to TB has yet emerged, and no studies have examined genetic influences on the early stages of Mtb infection. The present proposal utilizes patients and data collected through the Tuberculosis Research Unit (TBRU) NIH contract. Since 1995, we have been conducting a household contact study in Uganda where we are able to observe genetic and environmental risk factors for chronic Mtb infection and active TB disease. Our previous work has focused on genetic influences on the immune response and the spectrum of natural history of Mtb infection. We have shown that the TNFR1, IL10, and IFNGR1 genes are associated with TB but not resistance to Mtb infection. We have recently completed a genome scan that identified novel chromosomal regions, 2q21-2q24 and 5p13- 5q22, linked to resistance to Mtb. We have also identified innate immune response variables associated with progression to TB disease, but have not assessed immune factors associated with resistance to Mtb infection. Our preliminary results suggest that genetic and immune factors associated with resistance to Mtb infection versus TB disease development differ. Furthermore, we hypothesize that the complex interrelationships between host genes, innate immune response, and epidemiological factors combine to influence Mtb infection and progression to TB disease. To fully examine this complex network of genes and immune factors, we propose to construct a comprehensive pathway model. To this end, we propose three aims. First, we propose to fine map these novel chromosomal regions and analyze candidate genes in key immune pathways to identify genes associated with resistance to Mtb infection. Second, we propose to analyze a number of cytokines in response to innate immunity ligands to identify aspects of the innate immune response associated with resistance to Mtb infection. Third, we have developed a structural equation modeling framework appropriate for the analysis of family data, and we propose to analyze this data with that model and make software publicly available. We will analyze genetic and immunologic predictors of resistance to Mtb infection within the long-standing household contact study. This will also provide the first examination of resistance to Mtb infection; because of our thorough study design, we are uniquely poised to analyze this novel phenotype. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is a disease with great public health importance, with one-third of the world infected by M. tuberculosis (Mtb), and almost 8 million new cases of TB occur annually with 2 million deaths attributed to TB each year. Previous studies have shown a role for both genetic and immunologic factors that predispose to progression from Mtb infection to active TB disease, but these factors have not been analyzed simultaneously and have not identified factors associated with the "healthy" uninfected state. Findings of this project will expand knowledge of the joint genetic, epidemiologic, and immunologic influences on Mtb infection and TB disease, which will facilitate the development of improved vaccines and therapeutics.