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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肺炎（PNA）是肺移植（LTx）后死亡的主要原因。气管支气管炎 (TB) 是通常在怀疑呼吸道感染 (RTI) 的 LTx 接受者中得到诊断，并且诊断不符合 PNA 的标准。然而，LTx 情况下结核病确实的病理证据是缺乏，并且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 在没有感染的情况下，受体通常很难在临床上与定植区分开来（COL）。最近的基于 DNA 测序的微生物组分析研究表明，PNA 的特点是丢失下呼吸道微生物多样性以及优势病原体的出现。微生物组和宿主 LTx 后与 PNA、TB 或 COL 相关的反应标记尚未定义。在初步研究中，我们在支气管肺泡灌洗液 (BALF) 中发现了多变量、非培养特征来自 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 的特点是多样性丧失和强烈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。综合起来，初步数据表明 PNA 和 TB 源于不同的致病过程，并且微生物组和细胞因子分析可作为培养物和常规标准的诊断辅助手段。此举的目的该项目的目的是在 LTx 接收者中完善和验证 PNA、TB 和 COL 的多变量签名没有机械通风。在具体目标 1 中，我们将通过执行 16S 微生物组来完善特征分析细菌、评估呼吸道病毒的存在以及测量细胞因子反应 BALF 样本储存在我们的 LTx 生物样本库中。研究将通过以下方式扩展我们的初步数据每次诊断和检测呼吸道病毒和细菌时都需要大量样本，从而识别出更稳健、更能代表 LTx 群体的签名。我们将聘用我们的初步研究中开发了强大的多变量回归分析方法。在特定目标下 2，我们将使用来自实验室的一组独立的 BALF 样本来验证微生物组和细胞因子特征。生物储存库和从 LTx 接受者前瞻性收集的样本。据我们所知，我们是第一家小组描述了 LTx 接受者中 PNA、TB 和 COL 的微生物组和宿主反应基础。我们预计这项研究将为这些诊断定义优化的疾病特异性特征，这些特征是不取决于培养结果。该项目预计将进行多中心试验，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 的患者或社区获得性 PNA。此外，我们的结果将为可能的致病机制提供见解对于 LTx 后的 PNA 和 TB，这可以为后续的机制研究提供信息。