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集合体。他们 经历动态的环境依赖性变化。许多生物膜构成复杂的微生物群落 而不是由一个或几个物种组成的集合。在大多数体外生长条件下不可培养的菌种 条件可能有助于这些生物膜。世界上最常见的生物膜相关感染- 泌尿道感染（UTI）是一种常见的泌尿系统疾病。院内留置导管相关尿路感染（CA- 仅在美国，每年就有超过100万患者感染UTI。细菌定植于导管 高度适应于生物膜的产生。长期插入的细菌定植原因 导尿管导致CA-UTI与无症状菌尿（CA-ASB）的结果基本上是未知的， 可能涉及与宿主环境和微生物生物膜的复杂性有关的致病因素。 最近的16 S rRNA基因调查表明，CA生物膜和尿液中的微生物复杂性 沉淀物比以前认为的要高。本提案的总体目标是， 这些生物膜的动态形成和扩散，以及控制相对人类宿主惰性的触发因素 与炎症反应相比。我们假设，在致病性和致病性之间建立了动态平衡， 特征较少的通常无害的细菌，影响人类宿主的免疫反应的程度。 系统生物学方法允许整合不同的分子数据集，以阐明 负责合作和竞争行为的微生物物种，以及与尿路上皮宿主 防御系统第一个具体目标是分析CA的宏基因组、元蛋白组和代谢组 生物膜和分散的细菌聚集体从临床病例中的纵向研究设计。第二 具体目的是开发和评价接种CA生物膜分离株的体外模型系统， 对体外发育的生物膜进行组学分析。体外模型系统将基于培养 的CA生物膜分离物与控制水平的氧合和合成尿作为生长介质。第三 具体目标是整合和分析宏基因组，元蛋白质组和代谢组数据集使用 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特征 水平：物种、细菌和宿主蛋白质以及表征微生物模式的代谢物 在时域中相互通信，并允许评估宿主对和宿主 防御多细菌定植。我们预测这些结果不仅会产生深远的影响 关于生物膜动力学，但也将揭示与疾病相关的生物特征， 除CA-UTI外的一种传染性病原体。 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.