Longitudinal analysis of respiratory tract microbiome change and sequence-based infection diagnosis during mechanical ventilation

项目摘要 下呼吸道感染（LRTI）经常导致需要机械通气的呼吸衰竭。 呼吸机相关性肺炎是依赖呼吸机的患者的一种可怕的并发症。 机械通气尽管LRTI在重症监护中的临床重要性，但呼吸动力学 机械通气期间的肠道微生物组可能与感染和呼吸道感染的风险相对应。 定义LRTI的肠道微生物组特征仍然知之甚少。该研究将深入利用 对来自重症患者的上呼吸道和下呼吸道样本的16 S rRNA基因进行测序， 机械通气受试者，以提高对医疗保健相关微生物组的理解 变化，LRTI微生物生态学和LRTI发病机制。该研究将（1）定义纵向变化， 在机械通气期间发生在上呼吸道和下呼吸道细菌微生物组中;（2） 确定与临床相关的呼吸道微生物群落结构特征 LRTI的诊断和LRTI的缺乏;（3）评估16 S rRNA基因测序的能力， 鉴定导致LRTI的细菌病原体。这些具体目标的实现将阐明 健康护理暴露与呼吸道微生物组变化之间的关系，以及呼吸道微生物组变化与健康护理暴露之间的关系。 肠道微生物组变化和LRTI发病机制。因此，拟议的研究将为 在以患者为导向的研究中的独立职业，致力于提高对医疗保健的理解- 相关的微生物组变化和感染。目标的实现还将为主要研究者提供 具有指导大型观察性微生物组研究的基本经验，并在 先进的统计和生物信息学方法，分析患者水平之间的相互作用 因素（潜在疾病、抗生素暴露等）、微生物生态学和感染。研究建议 与职业发展计划相结合，利用大学的广泛资源， 宾夕法尼亚州，并利用导师委员会与广泛的，互补的专业知识， 传染病流行病学，卫生保健相关感染，深度测序方法，微生物学， 和重症监护艾宾劳滕巴赫博士弗雷德里克D.布什曼和罗纳德G.科尔曼将支持 主要研究者在概述的道路走向成功的职业生涯作为一个独立的临床研究者。

PROJECT SUMMARY Lower respiratory tract infection (LRTI) frequently contributes to respiratory failure that requires mechanical ventilation, and ventilator-associated pneumonia is a feared complication in patients dependent upon mechanical ventilation. Despite the clinical importance of LRTI in critical care, the dynamics of the respiratory tract microbiome during mechanical ventilation that may correspond with risk for infection and the respiratory tract microbiome features that define LRTI remain poorly understood. The proposed study will utilize deep sequencing of the 16S rRNA gene from upper and lower respiratory tract samples obtained from critically ill, mechanically ventilated subjects in order to improve understanding of healthcare-associated microbiome change, LRTI microbial ecology, and LRTI pathogenesis. The study will (1) define the longitudinal change that occurs in the upper and lower respiratory tract bacterial microbiome during mechanical ventilation; (2) determine the features of respiratory tract microbiome community structure that correlate with the clinical diagnosis of LRTI and with the absence of LRTI; and (3) evaluate the ability of 16S rRNA gene sequencing to identify bacterial pathogens responsible for LRTI. Execution of these specific aims will elucidate the relationships between healthcare exposures and respiratory tract microbiome change, and between respiratory tract microbiome change and LRTI pathogenesis. The proposed study will thus form a foundation for an independent career in patient-oriented research dedicated to improving understanding of healthcare- associated microbiome change and infection. Execution of the aims will also provide the primary investigator with essential experience directing a large, observational microbiome study and with essential training in the advanced statistical and bioinformatics methods necessary to analyze the interaction between patient-level factors (underlying disease, antibiotic exposure, etc), microbial ecology, and infection. The research proposal is paired with a career development plan that makes use of the extensive resources of the University of Pennsylvania, and which capitalizes on a mentorship committee with broad, complementary expertise in infectious diseases epidemiology, healthcare-associated infection, deep sequencing methods, microbiology, and critical care. Dr. Ebbing Lautenbach, Dr. Frederic D. Bushman, and Dr. Ronald G. Collman will support the primary investigator in the outlined path towards a successful career as an independent clinical investigator.