Proteogenomics of dysregulated protein interaction networks in MTB infection

描述（由申请人提供）：雾化结核分枝杆菌（MTB）很容易在人与人之间传播。分枝杆菌感染远端肺泡，在那里它们面对先天性反应不受约束地复制。随着适应性T细胞免疫的发展，MTB的生长得到控制，但杆菌没有被根除。T细胞与MTB感染的抗原呈递细胞（APC）之间的相互作用对于生物体逃避/抵抗宿主免疫以建立潜伏感染至关重要。在响应RFA-HL-10-015“TB潜伏和再激活机制的系统生物学方法”的这一申请中，我们汇集了蛋白质组学、计算机科学、生物信息学、遗传流行病学、流行病学、免疫学、肺生物学和肺医学，结合获得一组独特的流行病学和临床特征良好的MTB患者队列在美国、乌干达和S.非洲，以便将新的系统生物学方法应用于潜伏的MTB感染。最近的研究表明，蛋白质组学的方法，旨在确定蛋白质-蛋白质相互作用网络的结果，在疾病的发病机制中的作用的功能子网络的识别。我们建议将这种方法应用于人类潜伏性MTB感染（LTBI）的分析，并将蛋白质组学结果与使用人类遗传和全身性化学/细胞因子方法的平行研究联系起来，以了解MTB的发病机制。该提议的一般假设是，蛋白质组种子鉴定区分处于MTB感染和疾病的不同阶段的人的蛋白质的子网络，并提供对负责从LTBI进展到活动性TB的机制的深入了解。其目标是：目标1：确定与未发展为疾病的LTBI患者和发展为TB的患者相比，严重暴露于MTB的家庭中未被感染的人的单核吞噬细胞和CD 4 + T细胞中蛋白质-蛋白质相互作用亚网络失调。目标二：确定蛋白质-蛋白质相互作用子网络与全基因组和靶向基因分析之间的关系，以及通过多重化疗/细胞因子试验在与目标1相同的人群中检测到的外周化疗/细胞因子应答。目标3：确定目标1和2中分析的蛋白质-蛋白质相互作用和化学/细胞因子子网络中的哪一个与LTBI患者的肺CD 4 + T细胞和巨噬细胞最相关。 该提案将从美国、乌干达和南非流行病学特征良好的MTB感染者获得独特的临床标本（外周血细胞、血浆、支气管肺泡灌洗标本）与使用蛋白质组学、遗传流行病学和细胞因子生物学的专家结合起来，用于LTBI及其进展为活动性TB的多学科系统生物学方法。 公共卫生相关性：系统生物学非常适合分析人类和M之间复杂的相互作用。本发明的抗结核药物组合物是抗结核药物（MTB），其是结核病（TB）的原因，并且当应用于来自处于MTB暴露、感染和疾病的不同阶段的人的组织时特别有效。利用系统生物学来寻找受结核分枝杆菌暴露或感染干扰的关键宿主蛋白质，使我们能够识别有进展为活动性结核病风险的人，并找出我们需要自然或通过接种疫苗来保护免受结核病的影响。

DESCRIPTION (provided by applicant): Aerosolized Mycobacterium tuberculosis (MTB) is readily transmitted from person to person. Mycobacteria infect the distal alveoli where they replicate unfettered in the face of innate responses. As adaptive T cell immunity develops, MTB growth is controlled but bacilli are not eradicated. The interactions between T cells and MTB infected antigen presenting cells (APC) are central for the organism to evade/resist host immunity to establish latent infection. In this application in response to RFA-HL-10-015 "Systems Biology Approach to the Mechanisms of TB Latency and Reactivation" we bring together a multidisciplinary team of experts in proteomics, computer science, bioinformatics, genetic epidemiology, epidemiology, immunology, lung biology and pulmonary medicine coupled to access to a unique set of cohorts of epidemiologically and clinically well characterized persons with the spectrum of MTB exposure, infection and disease in the US, Uganda and S. Africa, in order to apply novel systems biology approaches to latent MTB infection. Recent studies suggest that proteomic approaches aimed at identifying protein-protein interaction networks result in the identification of functional sub-networks with a role in disease pathogenesis. We propose to apply this approach to the analysis of latent MTB infection (LTBI) in humans, and to link proteomic results with parallel studies using human genetic and systemic chemo-/cytokine approaches to understanding MTB pathogenesis. The general hypothesis of this proposal is that proteomic seeds identify sub-networks of proteins that differentiate persons at different stages of MTB infection and disease, and provide insight into the mechanism(s) responsible for progression from LTBI to active TB. The aims are: Aim 1: To determine dysregulated protein-protein interaction sub-networks in mononuclear phagocytes and CD4+ T cells of persons in households heavily exposed to MTB who do not become infected compared to those with LTBI who do not progress to disease and those who develop TB. Aim 2: To determine the relationship between protein-protein interaction sub-networks to whole genome and targeted gene analyses, and peripheral chemo-/cytokine responses detected by multiplex chemo-/cytokine assays in the same population as in Aim 1. Aim 3: To determine which of the protein-protein interaction and chemo-/cytokine sub-networks analyzed in Aims 1 and 2 are most relevant for lung CD4+ T cells and macrophages from persons with LTBI. This proposal combines access to unique clinical specimens (peripheral blood cells, plasma, broncho- alveolar lavage specimens) from epidemiologically well characterized persons with MTB infection in US, Uganda and South Africa with experts in the use of proteomics, genetic epidemiology and cytokine biology for a multidisciplinary systems biology approach to LTBI and its progression to active TB. PUBLIC HEALTH RELEVANCE: Systems biology is ideally suited to analyze the complex interaction between humans and M. tuberculosis (MTB), the cause of tuberculosis (TB), and is particularly powerful when applied to tissues from persons in different stages of MTB exposure, infection and disease. Using systems biology to find key host proteins disturbed by MTB exposure or infection allows us to identify persons at risk for progression to active TB and find out what we need to be naturally or through vaccination protected against TB.