The Microbiome, Virome and Host Responses Preceding Ventilator-Associated Pneumon

呼吸机相关肺炎发生前的微生物组、病毒组和宿主反应

基本信息

批准号：
8764528
负责人：
PETER M MOURANI
金额：
$ 76.89万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764528
关键词：
Animals Aspirate substance Bacteria Bacterial Infections Behavior Biological Markers Child Clinical Complication Critically ill children Data Development Diagnostic Disease Ecological Change Ecology Environment Equilibrium Evaluation Genomics Human Immune Immune response Immunologics Immunosuppression Individual Infection Integration Host Factors Intensive Care Units Interdisciplinary Study Interferons Interleukin-10 Intubation Investigation Lead Life Lower Respiratory Tract Infection Lung Measures Mechanical ventilation Mediating Mediator of activation protein Methodology Molecular Morbidity - disease rate Nosocomial Infections Nucleic Acids Organism Outcome Pathogenesis Pathway interactions Patients Pattern Plasma Play Pneumonia Population Prevention Prevention strategy Process Proteomics Public Health Rehabilitation therapy Relative (related person)Resources Respiratory Failure Risk Risk Factors Role Sampling Scientist Secondary to Sterility Techniques Testing Therapeutic Translating Ventilator Viral Virulence Virus Diseases cost deep sequencing endotracheal experience high risk immune activation improved innovation insight microbial microbial host microbiome microorganism mortality novel novel strategies pathogen prevent public health relevance respiratory response superinfection treatment strategy virome

项目摘要

DESCRIPTION (provided by applicant): Ventilator-associated pneumonia (VAP) is a serious complication in mechanically ventilated children, increasing risk of mortality and morbidities including prolonged intubation and intensive care unit stays. Limited understanding of the microbial and host factors associated with VAP has precluded development of truly effective prevention and treatment strategies. Recent evidence has revealed that the lungs, previously considered sterile, contain microbial populations. These endogenous bacteria are likely critical regulators of both pathogen behavior and host responses in the airways, modulating the virulence of potential pathogens. In addition, respiratory failure secondary to viral lower respiratory tract infections is common among children and is often complicated by bacterial co-infections, including VAP. Yet, standard bacterial and viral culture methodologies are inefficient and insensitive for identifying the full spectrum of airway microorganisms associated with VAP. New methodologies are needed to better understand the pathogenesis of VAP. Study of the microbiome, the genomic content of the microbiota (the organisms living in an environment), is a novel approach to describe the complexities of the airway microbiota. Culture-independent molecular techniques, using nucleic acids isolated from routinely collected respiratory samples, can provide sensitive quantification of the bacterial and viral constituents of the microbiome elucidating ecological changes that may precede development of VAP. Viral infections may alter the endogenous flora and may also activate host immune suppressive responses that lead to less effective control of bacterial populations and subsequent bacterial infection. However, there has not been a systematic evaluation of virome-bacterial microbiome interactions in this population. We hypothesize that specific ecological patterns of the airway microbiome precede VAP and that the interaction of viral infection, bacterial populations, and the balance between host immune activation and immune suppression play crucial roles in determining whether a given patient develops VAP. We propose to investigate this hypothesis with a longitudinal (daily) examination of the airway microbiome in high risk mechanically ventilated children together with simultaneous proteomic assessments of the host immune response. Aim 1 of this proposal will characterize the changes in the airway microbiome of mechanically ventilated patients that precede the development of VAP. Aim 2 will determine whether respiratory viral infections interact with the airway microbiome to promote changes in the microbiota associated with VAP. Aim 3 will explore the molecular and immunologic mechanisms by which these viral-bacterial interactions promote lung infection, and will test the specific hypothesis that virally-induced hos immune suppressive pathways are preferentially up-regulated in those patients who develop VAP. This project will provide insight into the pathogenesis of VAP, uncover unique biomarkers of disease, and identify potential targets for novel prevention and treatment strategies. 1

描述（由申请人提供）：呼吸机相关性肺炎 (VAP) 是机械通气儿童的一种严重并发症，会增加死亡和发病的风险，包括延长插管时间和重症监护病房住院时间。对与 VAP 相关的微生物和宿主因素的了解有限，阻碍了真正有效的预防和治疗策略的制定。最近的证据表明，以前被认为是无菌的肺部含有微生物群。这些内源性细菌可能是呼吸道中病原体行为和宿主反应的关键调节因子，调节潜在病原体的毒力。此外，病毒性下呼吸道感染继发的呼吸衰竭在儿童中很常见，并且常常因细菌合并感染（包括 VAP）而并发。然而，标准细菌和病毒培养方法对于识别与 VAP 相关的全谱气道微生物而言效率低下且不敏感。需要新的方法来更好地了解 VAP 的发病机制。微生物组研究，即微生物群（生活在环境中的生物体）的基因组内容，是描述气道微生物群复杂性的一种新方法。不依赖于培养物的分子技术，使用从常规收集的呼吸道样本中分离的核酸，可以对微生物组的细菌和病毒成分进行灵敏的定量，从而阐明 VAP 发生之前可能发生的生态变化。病毒感染可能会改变内源性菌群，也可能激活宿主免疫抑制反应，导致对细菌种群的控制效果较差，进而导致细菌感染。然而，尚未对该人群中的病毒组-细菌微生物组相互作用进行系统评估。我们假设气道微生物组的特定生态模式先于 VAP，并且病毒感染、细菌种群的相互作用以及宿主免疫激活和免疫抑制之间的平衡在确定特定患者是否发生 VAP 方面发挥着至关重要的作用。我们建议通过对高危机械通气儿童的气道微生物组进行纵向（每日）检查，同时对宿主免疫反应进行蛋白质组学评估来研究这一假设。该提案的目标 1 将描述机械通气患者在发生 VAP 之前气道微生物组的变化。目标 2 将确定呼吸道病毒感染是否与气道微生物群相互作用，从而促进与 VAP 相关的微生物群发生变化。目标 3 将探索这些病毒-细菌相互作用促进肺部感染的分子和免疫学机制，并将检验病毒诱导的宿主免疫抑制途径在发生 VAP 的患者中优先上调的具体假设。该项目将深入了解 VAP 的发病机制，发现疾病的独特生物标志物，并确定新的预防和治疗策略的潜在目标。 1