Expression signatures of TB-specific memory responses within the human lung

人肺内结核病特异性记忆反应的表达特征

• 批准号: 8579599
• 负责人: RICHARD F SILVER
• 金额: $ 67.45万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-07 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579599
• 关键词: Address; Antigens; Attenuated; BCG Vaccine; Back; Bacteria; Bioinformatics; Blood Circulation; Breathing; Bronchoalveolar Lavage; Bronchoscopy; CD4 Positive T Lymphocytes; Calmette-Guerin Bacillus; Cells; Cellular Immunity; Child; Collaborations; Containment; Dana-Farber Cancer Institute; Development; Disease; Event; Exposure to; Gene Expression; Gene Expression Profile; Genes; Goals; Homing; Human; Hypersensitivity skin testing; Immune; Immune response; Immunity; Immunophenotyping; Individual; Infection; Infection Control; International; Investigation; Lung; Lymphocyte; Measures; Mediating; Memory; Methodology; Microarray Analysis; Modeling; Molecular Profiling; Mucosal Immune Responses; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Oral; Organism; Phenotype; Population; Population Study; Procedures; Process; Production; Property; Protocols documentation; Public Health; Pulmonary Tuberculosis; Reagent; Recruitment Activity; Research; Research Personnel; Respiratory Tract Infections; Role; Route; Saints; Sampling; Silver; T memory cell; T-Lymphocyte; Technology; Time; Tissues; Tuberculosis; Tuberculosis Vaccines; Universities; Vaccinated; Vaccination; Virulent; base; chemokine; cohort; cytokine; experience; gene induction; genome-wide; improved; novel; particle; pathogen; peripheral blood; prevent; programs; public health relevance; respiratory; response; tuberculin purified protein derivative; vaccination against tuberculosis; vaccination strategy

DESCRIPTION (provided by applicant): Tuberculosis (TB) remains a significant threat to international public health, as over 2 million individuals die of the disease each year. Mycobacterium tuberculosis (Mtb), the organism that causes TB, is a respiratory pathogen spread via inhalation of infectious airborne particles. Better understanding of local immunity to Mtb within the human lung is critical to development of more effective TB vaccination programs, and, more generally, to understanding the mechanisms by which cell-mediated immunity functions within the human lung. Our research team represents a unique collaboration of investigators with experience in bronchoscopy-based studies of human immunity to Mtb (Richard Silver, Case Western Reserve University) assessment of immune responses to experimental TB vaccination (Daniel Hoft, Saint Louis University) and immunological bioinformatics analysis (Vladimir Brusic, Dana Farber Cancer Institute). The overall goals of this proposal are to define the mechanisms that mediate protective local immunity to Mtb within the human lung, and to clarify the basis for the suboptimal efficacy of current TB vaccination with the attenuated Mycobacterium bovis strain the Bacillus of Calmette and Guerin (BCG). Understanding immunity to Mtb within the lung is of particular importance because although current intradermal (ID) BCG vaccination protects against disseminated forms of TB, it does not provide adequate protection against the most contagious form of the disease, pulmonary TB. We propose to apply genome-wide microarray analysis to evaluate the Mtb-induced transcriptome of cells obtained from the lung via bronchoalveolar lavage (BAL). Our preliminary studies indicate that global Mtb-induced gene expression of BAL cells from healthy subjects with latent tuberculosis infection (LTBI) following respiratory infection with the organism is markedly different from that of Mtb-naive subjects. These differences suggest that resident Mtb-specific effector memory T cells (TEM) present in baseline BAL have a profound impact on expression of the pulmonary transcriptome. This memory response includes promotion of rapid chemokine production as well as induction of genes involved in multiple processes that may potentially impact the viability of intracellular Mtb. We will also compare the Mtb-induced transcriptomes of baseline BAL cells from individuals with LTBI to those obtained from a unique cohort of subjects vaccinated with BCG either by the standard ID route, or by oral (PO) administration. In addition, we will assess the impact of this early chemokine production on recruitment of additional immune cells to the lung using a novel protocol of segmental bronchoscopic challenge with the skin-test reagent purified protein derivative of Mtb (PPD). PPD challenge serves as a model of local immune events following respiratory re-exposure to Mtb, and will allow us to compare the Mtb-induced transcriptome of these recruited cells to those of baseline BAL. Correlation of these gene expression findings with measures of inhibition of virulent Mtb will allow us determine the mechanisms by which cell recruitment enhances containment of Mtb within the lungs of both LTBI subjects and BCG vaccine recipients. These studies will therefore address the following Specific Aims: 1) To determine the mechanisms by which specific cytokines and T-cell populations contribute to the localized immunophenotype of pulmonary recall responses to Mycobacterium tuberculosis. 2) To evaluate potential mechanisms by which BCG vaccination may provide suboptimal development of M. tuberculosis-specific immunity within the human lung; and 3) To evaluate the processes by which cells recruited to the lung in response to re-exposure to M. tuberculosis antigens enhance containment of the organism in both Mtb-infected and BCG-vaccinated individuals.

描述（由申请人提供）：结核病（TB）仍然是对国际公共卫生的重大威胁，每年有200多万人死于该病。结核分枝杆菌（Mtb）是引起结核病的生物体，是一种通过吸入传染性空气传播颗粒传播的呼吸道病原体。更好地了解人肺内对结核分枝杆菌的局部免疫，对于制定更有效的结核病疫苗接种规划，以及更普遍地了解细胞介导的免疫在人肺内发挥作用的机制至关重要。我们的研究团队代表了具有基于支气管镜的人类对结核分枝杆菌免疫研究（Richard Silver， Case Western Reserve大学）、实验性结核疫苗免疫反应评估（Daniel Hoft，圣路易斯大学）和免疫生物信息学分析（Vladimir Brusic， Dana Farber癌症研究所）经验的研究人员的独特合作。本提案的总体目标是确定介导人肺内对结核分枝杆菌的保护性局部免疫的机制，并阐明目前用牛分枝杆菌减毒菌株卡介苗（BCG）接种结核疫苗效果不佳的基础。了解对肺内结核分枝杆菌的免疫力尤为重要，因为尽管目前的皮内卡介苗疫苗可以预防播散性结核，但它不能对最具传染性的结核病——肺结核——提供充分的保护。我们建议应用全基因组微阵列分析来评估通过支气管肺泡灌洗（BAL）获得的肺细胞的mtb诱导转录组。我们的初步研究表明，呼吸道感染后健康的潜伏性结核感染（LTBI）患者的BAL细胞在mtb诱导下的整体基因表达明显不同于未感染mtb的受试者。这些差异表明，基线BAL中存在的常驻mmb特异性效应记忆T细胞（TEM）对肺转录组的表达有深远的影响。这种记忆反应包括促进快速趋化因子的产生以及诱导参与可能潜在影响细胞内结核分枝杆菌生存能力的多个过程的基因。我们还将比较LTBI患者的基线BAL细胞的mb诱导转录组与通过标准ID途径或口服（PO）接种卡介苗的独特队列受试者的转录组。此外，我们将评估这种早期趋化因子的产生对肺部募集额外免疫细胞的影响，使用皮肤试验试剂纯化的Mtb蛋白衍生物（PPD）进行段性支气管镜攻击的新方案。PPD挑战可作为呼吸再次暴露于Mtb后局部免疫事件的模型，并将使我们能够比较Mtb诱导的这些募集细胞的转录组与基线BAL的转录组。这些基因表达结果与毒性Mtb抑制措施的相关性将使我们能够确定细胞募集增强LTBI受试者和卡介苗接种者肺部Mtb抑制的机制。因此，这些研究将解决以下具体目标：1)确定特定细胞因子和t细胞群对结核分枝杆菌肺召回反应的局部免疫表型的作用机制。2)评估卡介苗接种可能导致人肺内结核分枝杆菌特异性免疫次优发展的潜在机制；3)评估在mtb感染和bcg接种个体中，重新暴露于结核分枝杆菌抗原后聚集到肺部的细胞增强对结核菌的遏制作用的过程。