Microbiome and host response signatures for pneumonia among lung transplant recipients

肺移植受者肺炎的微生物组和宿主反应特征

• 批准号: 9168095
• 负责人: CORNELIUS J CLANCY
• 金额: $ 21.65万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9168095
• 关键词: Acute; Area; Bacteria; Bacterial Pneumonia; Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Cause of Death; Cells; Chronic; Communicable Diseases; Communities; Complex; DNA Sequence; Data; Diagnosis; Diagnostic; Disease; Ecosystem; Goals; Guidelines; Immune; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response Pathway; Lead; Lower respiratory tract structure; Lung; Lung Transplantation; Measures; Methodology; Multicenter Trials; Outcome Study; Pathogenesis; Pathologic; Patients; Pneumonia; Population; Process; Receiver Operating Characteristics; Regression Analysis; Research; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Ribosomal RNA; Sampling; Signs and Symptoms; Syndrome; Testing; Transplant Recipients; Transplantation; Ventilator; base; biobank; cytokine; inflammatory marker; insight; member; microbial; microbiome; microbiota; pathogen; respiratory virus; response; response biomarker; stem; validation studies; ventilator-associated pneumonia

Project Summary Pneumonia (PNA) is a leading cause of death following lung transplantation (LTx). Tracheobronchitis (TB) is commonly diagnosed in LTx recipients in whom a respiratory tract infection (RTI) is suspected, and diagnostic criteria for PNA are not fulfilled. However, conclusive pathologic evidence for TB in the setting of LTx is lacking, and it is unclear that the diagnosis constitutes a coherent disease entity. Moreover, RTIs in LTx recipients are often difficult to distinguish clinically from colonization in the absence of infection (COL). Recent DNA sequencing-based microbiome profiling studies have revealed that PNA is characterized by loss of microbial diversity in the lower respiratory tract, and emergence of a dominant pathogen. Microbiome and host response markers that are associated with PNA, TB or COL following LTx are undefined. In preliminary studies, we identified multivariable, non-culture-based signatures within bronchoalveolar lavage fluid (BALF) samples from LTx recipients that distinguished PNA and TB from COL, which were comprised of 16S microbiome and cytokine covariates. Compared to COL, PNA was characterized by loss of diversity and a robust pro-inflammatory cytokine response. In contrast, TB was characterized by high microbial diversity and multifunctional cytokine responses that differed from those of PNA. Taken together, the preliminary data suggest that PNA and TB stem from different pathogenic processes, and that microbiome and cytokine profiling may have utility as diagnostic adjuncts to cultures and conventional criteria. The objective of this project is to refine and validate multivariable signatures for PNA, TB and COL among LTx recipients who are not mechanically ventilated. In specific aim 1, we will refine the signatures by performing 16S microbiome profiling for bacteria, assessing the presence of respiratory viruses, and measuring cytokine responses in BALF samples that are banked in our LTx biorepository. Studies will expand upon our preliminary data by including a larger number of samples for each diagnosis and detecting respiratory viruses as well as bacteria, thereby identifying signatures that are more robust and representative of the LTx population. We will employ powerful multivariable regression analysis methodologies developed in our preliminary studies. In specific aim 2, we will validate microbiome and cytokine signatures, using an independent set of BALF samples from the biorepository and samples collected prospectively from LTx recipients. To our knowledge, we are the first group to describe the microbiome and host response underpinnings of PNA, TB and COL in LTx recipients. We anticipate that this study will define optimized, disease-specific signatures for these diagnoses, which are not contingent upon culture results. The project is expected to lead to multi-center trials validating the signatures, and to studies in settings outside of LTx, such as among patients with ventilator-associated RTIs or community-acquired PNA. Furthermore, our results will provide insights into possible pathogenic mechanisms for PNA and TB following LTx, which can inform subsequent mechanistic studies.

项目摘要 肺炎(PNA)是肺移植(LTX)后的主要死亡原因。支气管炎(TB)是 通常在疑似呼吸道感染(RTI)的LTX接受者中诊断，并诊断为 没有满足PNA的标准。然而，在LTX的背景下，结核病的确凿病理证据是 缺乏，目前尚不清楚诊断是否构成一个连贯的疾病实体。此外，LTX中的RTI 受体通常很难在临床上与无感染时的定植(COL)区分开来。近期 基于DNA测序的微生物组图谱研究表明，PNA的特征是 下呼吸道的微生物多样性，以及一种主要病原体的出现。微生物群与寄主 未定义与LTX之后的PNA、TB或COL相关联的响应标记。在预赛中 研究中，我们确定了支气管肺泡灌洗液(BALF)中的多变量、非培养信号。 来自LTX接受者的样本将PNA和TB与Col区分开来，这些样本由16S组成 微生物组和细胞因子协变量。与COL相比，PNA的特征是多样性的丧失和 强大的促炎细胞因子反应。相比之下，结核病的特点是微生物多样性高， 与PNA不同的多功能细胞因子反应。综合来看，初步数据 提示PNA和TB来源于不同的致病过程，微生物组和细胞因子 作为培养和常规标准的辅助诊断，侧写可能具有实用价值。这样做的目的是 项目是完善和验证PNA、TB和COL在LTX接受者中的多变量签名，这些接受者是 非机械通风的。在具体目标1中，我们将通过执行16S微生物组来提炼签名 分析细菌，评估呼吸道病毒的存在，并测量细胞因子反应 储存在我们LTX生物储存库的BALF样本。研究将在我们初步数据的基础上扩大到 包括每次诊断和检测呼吸道病毒和细菌的更多样本， 从而识别更稳健且更能代表LTX群体的签名。我们将聘用 在我们的初步研究中开发了强大的多变量回归分析方法。以特定的目标 2，我们将使用一组独立的BALF样本验证微生物组和细胞因子签名 生物信息库和预期从LTX接受者那里收集的样本。据我们所知，我们是第一个 小组描述PNA、TB和COL在LTX接受者中的微生物群和宿主反应基础。 我们预计这项研究将为这些诊断定义优化的、特定于疾病的特征，这些特征是 不取决于文化结果。该项目预计将导致多中心试验验证 签名，以及在LTX之外的环境中进行的研究，例如在患有呼吸机相关RTI或 社区获得的PNA。此外，我们的结果将为可能的致病机制提供见解。 对于PNA和TB，LTX之后，这可以为后续的机制研究提供信息。