Urethral Catheter-Associated Polybacterial Biofilm Formation and Dispersal

生物膜是附着在非生物和生物表面的基质封闭的微生物组件。他们 经历与环境相关的动态变化。许多生物膜构成了复杂的微生物群落。 而不是由一个或几个物种组成的集合体。在大多数试管生长条件下无法栽培的物种 条件可能对这些生物膜有影响。最常见的生物被膜相关感染世界- 广泛的是尿路感染(UTI)。医院留置导尿管相关性尿路感染 仅在美国，每年就有100多万患者感染UTI)。细菌在导管中定植 高度适应生物膜的生产。细菌长期植入后定植的原因 导尿管在CA-UTI和无症状菌尿(CA-ASB)中的结果基本上是未知的，并且 与宿主环境和微生物生物膜的复杂性有关的致病因素可能是牵连的。 最近的16S rRNA基因研究表明，CA生物膜和尿液中微生物的复杂性 沉淀物比之前认为的要高。这项提案的总体目标是描述 这些生物膜的动态形成和扩散，以及控制相对人类宿主惯性的触发因素 而不是炎症反应。我们假设在致病和致病之间建立了动态平衡 不太典型的一般无害的细菌，影响人类宿主免疫反应的程度。 系统生物学方法允许集成不同的分子数据集来阐明 负责合作和竞争行为的微生物种类以及与尿路上皮宿主的关系 防御系统。第一个具体目标是对CA的元基因组、代谢蛋白质组和代谢组进行分析 来自临床病例的生物被膜和分散的细菌聚集体的纵向研究设计。第二 具体目的是开发和评估接种CA生物被膜分离株和 对体外形成的生物膜进行组学分析。体外模型系统将以培养为基础 以人工尿液为生长介质，控制氧合水平的CA生物被膜分离株。第三 具体目标是使用以下工具整合和分析元基因组、元蛋白质组和代谢组数据集 先进的生物信息学和多元统计方法。我们打算在五个不同的地方识别生物签名 水平：表征微生物模式的物种、细菌和宿主蛋白及代谢物 在时间域中相互通信，并允许评估主机对和主机的容忍度 防御多细菌定植。我们预测，这一结果不仅将产生深远的影响 关于生物膜动力学，但也将揭示与疾病相关的生物特征，而不限于 一种非CA-UTI的感染性病原体。 2.

Biofilms are matrix-enclosed microbial assemblies adhering to non-biological and biological surfaces. They undergo dynamic environment-dependent changes. Many biofilms constitute complex microbial communities rather than assemblies composed of one or a few species. Species uncultivable under most in vitro growth conditions may contribute to these biofilms. The most frequently occurring biofilm-associated infection world- wide is the urinary tract infection (UTI). Nosocomial indwelling catheter-associated urinary tract infections (CA- UTI) are contracted by more than 1 million patients per year in the U.S. alone. Bacteria colonizing the catheters are highly adapted to the production of biofilms. Reasons as to why bacterial colonization of long term-inserted urethral catheters results in CA-UTI versus asymptomatic bacteriuria (CA-ASB) are essentially not known, and causative factors pertaining to the host environment and complexity of microbial biofilms may be implicated. Recent 16S rRNA gene surveys have indicated that microbial complexity of CA biofilms and urinary precipitates is higher than previously thought. The overall objective of this proposal is to characterize the dynamic formation and dispersal of these biofilms, as well as the triggers controlling relative human host inertia versus inflammatory responses. We hypothesize thata dynamic balance is established among pathogenic and lesser-characterized generally harmless bacteria, influencing the extent of the human host's immune response. A systems biology approach allows integration of diverse molecular datasets to elucidate signaling among microbial species responsible for cooperative as well as competitive behaviors and with the urothelial host defense system. The first Specific Aim is to profile the metagenome, metaproteome and metabolome of CA biofilms and dispersed bacterial aggregates from clinical cases in a longitudinal study design. The second Specific Aim is to develop and evaluate in vitro model systems inoculated with CA biofilm isolates and perform 'omics analysis on in vitro developing biofilms. The in vitro model systems will be based on cultivation of CA biofilm isolates with controlled level of oxygenation and synthetic urine as growth media. The third Specific Aim is to integrate and analyze metagenomic, metaproteomic and metabolomic datasets using advanced bioinformatics and multivariate statistics methods. We intend to identify biosignatures at five different levels: species, bacterial and host proteins and metabolites that characterize patterns of microbial communication with each other in the time domain and allow assessments of host tolerance towards and host defense against polybacterial colonization. We predict that the results will not only have profound implications as regards biofilm dynamics, but will also reveal biosignatures relevant in the context of diseases not limited to one infectious agent other than CA-UTI. 2.