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

• 批准号: 9290958
• 负责人: PETER M MOURANI
• 金额: $ 63.58万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9290958
• 关键词: Animals; Aspirate substance; Bacteria; Bacterial Infections; Biological Markers; Child; Clinical; Complication; Critically ill children; Data; Development; Disease; Ecological Change; Ecology; Environment; Equilibrium; Evaluation; Genomics; Human; Immune; Immune response; Immunologics; Immunosuppression; Individual; Infection; Inflammasome; Integration Host Factors; Intensive Care Units; Interdisciplinary Study; Interferons; Interleukin-10; Intubation; Investigation; Lead; Lower Respiratory Tract Infection; Lung; Measures; Mechanical ventilation; Mechanics; Mediating; Mediator of activation protein; Methodology; Molecular; Morbidity - disease rate; Nosocomial Infections; Nucleic Acids; Organism; Pathogenesis; Pathway interactions; Patients; Pattern; Plasma; Play; Pneumonia; Population; Prevention; Prevention strategy; Process; Proteomics; Public Health; Rehabilitation therapy; Resources; Respiratory Failure; Risk; Risk Factors; Role; Sampling; Scientist; Secondary to; Sterility; Techniques; Testing; Therapeutic; Translating; Ventilator; Viral; Viral Respiratory Tract Infection; Virulence; Virus Diseases; behavioral response; biomarker panel; co-infection; cost; deep sequencing; endotracheal; experience; high risk; immune activation; improved; improved outcome; innovation; insight; microbial; microbial host; microbiome; microbiota; microorganism; molecular diagnostics; mortality; novel; novel marker; novel strategies; pathogen; prevent; public health relevance; respiratory; response; superinfection; treatment strategy; ventilator-associated pneumonia; virome

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）：呼吸机相关的肺炎（VAP）是机械通气儿童的严重并发症，增加了死亡率和病态的风险，包括长时间的插管和重症监护病房。对与VAP相关的微生物和宿主因素的了解有限，无法发展真正有效的预防和治疗策略。最近的证据表明，以前认为无菌的肺包含微生物种群。这些内源性细菌可能是病原体行为和气道中宿主反应的关键调节剂，从而调节潜在病原体的毒力。此外，儿童中继发于病毒下呼吸道感染继发的呼吸道衰竭是常见的，通常因细菌共感染（包括VAP）而变得复杂。然而，标准细菌和病毒培养方法效率低下且不敏感，可识别与VAP相关的全部气道微生物。需要新的方法来更好地了解VAP的发病机理。对微生物组的研究，即微生物群的基因组含量（生活在环境中的生物），是一种描述气道微生物群复杂性的新方法。培养的非依赖性分子技术，使用从常规收集的呼吸样品中分离出的核酸，可以对微生物组阐明生态变化的细菌和病毒成分的敏感定量，这可能是在VAP的发展之前。病毒感染可能会改变内源性菌群，还可能激活宿主免疫抑制反应，从而导致细菌群体和随后的细菌感染的有效控制较低。但是，尚未系统地评估该人群中的病毒 - 细菌微生物组相互作用。我们假设气道微生物组的特定生态模式在VAP之前，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给定患者是否发展为VAP方面起着至关重要的作用。我们建议通过对高风险的机械通风儿童的气道微生物组进行纵向（每日）检查以及同时对宿主免疫反应的蛋白质组学评估，以研究这一假设。该提案的目标1将表征在VAP发展之前的机械通风患者气道微生物组的变化。 AIM 2将确定呼吸道病毒感染是否与气道微生物组相互作用，以促进与VAP相关的微生物群的变化。 AIM 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，并将测试特定的假设，即病毒诱导的HOS免疫抑制途径在那些患有VAP的患者中优先上调。该项目将洞悉VAP的发病机理，发现独特的疾病生物标志物，并确定新型预防和治疗策略的潜在靶标。 1

项目成果

Molecular analysis of endotracheal tube biofilms and tracheal aspirates in the pediatric intensive care unit.

儿科重症监护病房气管插管生物膜和气管抽吸物的分子分析。

• DOI: 10.12715/apr.2017.4.14
• 发表时间: 2017
• 期刊: Advances in pediatric research
• 作者: Leroue,MatthewK;Harris,JKirk;Burgess,KatherineM;Stevens,MarkJ;Miller,JoshuaI;Sontag,MarciK;Sierra,YamilaL;Wagner,BrandieD;Mourani,PeterM
• 通讯作者: Mourani,PeterM