Proteogenomics of dysregulated protein interaction networks in MTB infection

MTB 感染中失调的蛋白质相互作用网络的蛋白质基因组学

• 批准号: 8525430
• 负责人: W. Henry Boom
• 金额: $ 65.1万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525430
• 关键词: Africa; Alveolar; Alveolus; Antigen-Presenting Cells; Bacillus (bacterium); Bioinformatics; Biological; Biological Assay; Biology; Blood Cells; CD4 Positive T Lymphocytes; Cells; Chronic; Clinical; Colon Carcinoma; Complex; Coupled; Disease; Distal; Epidemiology; Exposure to; Gene Targeting; Genome; Genus Mycobacterium; Growth; HIV; Household; Human; Human Genetics; Immune response; Immunity; Immunology; Infection; Irrigation; Learning; Link; Lung; Malignant - descriptor; Malignant Neoplasms; Mononuclear; Mycobacterium tuberculosis; Non-Malignant; Ohio; Organism; Pathogenesis; Pathologic; Pattern; Peripheral; Persons; Phagocytes; Phenotype; Plasma; Population; Proteins; Proteome; Proteomics; Pulmonology; Research Personnel; Risk; Role; Sampling; Seeds; South Africa; Specimen; Staging; Systems Biology; T-Lymphocyte; Tissues; Tuberculosis; Uganda; Vaccination; Validation; aerosolized; case control; cohort; computer science; cytokine; genetic epidemiology; innovation; insight; latent infection; macrophage; multidisciplinary; novel; novel strategies; peripheral blood; protein protein interaction; public health relevance; reactivation from latency; response; transcriptomics; tumor

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.

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，在那里它们在面对先天反应时不受限制地复制。随着适应性 T 细胞免疫的发展，MTB 的生长受到控制，但杆菌并未被根除。 T 细胞和 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。在本申请中，为了响应 RFA-HL-10-015“结核病潜伏期和再激活机制的系统生物学方法”，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、肺病学等领域的多学科专家团队。生物学和肺医学相结合，可以接触到一组独特的流行病学和临床特征良好的人群，这些人群具有 MTB 暴露、感染和疾病的范围美国、乌干达和南非，旨在将新的系统生物学方法应用于潜在的结核分枝杆菌感染。最近的研究表明，旨在识别蛋白质-蛋白质相互作用网络的蛋白质组学方法可以识别在疾病发病机制中发挥作用的功能子网络。我们建议将此方法应用于人类潜伏 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化学/细胞因子方法的平行研究联系起来，以了解 MTB 发病机制。该提案的总体假设是，蛋白质组学种子可识别蛋白质子网络，这些蛋白质子网络可区分处于 MTB 感染和疾病不同阶段的人，并提供对从 LTBI 进展为活动性 TB 的机制的深入了解。目标是： 目标 1：确定家庭中严重暴露于 MTB 且未受到感染的人的单核吞噬细胞和 CD4+ T 细胞中失调的蛋白质-蛋白质相互作用子网络，与患有 LTBI 且未进展为疾病的人和那些患有结核病的人。目标 2：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，以及在与目标 1 相同的人群中通过多重化学/细胞因子测定检测到的外周化学/细胞因子反应之间的关系。 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/细胞因子子网络中哪些与人肺 CD4+ T 细胞和巨噬细胞最相关与 LTBI 一起。 该提案将美国、乌干达和南非流行病学特征明确的 MTB 感染者的独特临床标本（外周血细胞、血浆、支气管肺泡灌洗标本）与利用蛋白质组学、遗传流行病学和细胞因子生物学的专家结合起来，针对 LTBI 及其发展为活动性结核病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与结核分枝杆菌 (MTB)（结核病 (TB) 的病因）之间复杂的相互作用，并且当应用于处于 MTB 暴露、感染不同阶段的人的组织时，其作用尤其强大和疾病。利用系统生物学来寻找受 MTB 暴露或感染干扰的关键宿主蛋白，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疫苗接种来预防结核病。