Proteus mirabilis swarming: Initiation and role during urinary tract infection

奇异变形杆菌群聚：尿路感染过程中的启动和作用

• 批准号: 8395251
• 负责人: Chelsie Elizabeth Armbruster
• 金额: $ 4.92万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395251
• 关键词: Accounting; Address; Agar; Amino Acids; Anabolism; Antibiotic Therapy; Arginine; Bacteria; Behavior; Biophotonics; Bladder Calculi; Carbon; Catheterization; Catheters; Cell Density; Cell Differentiation process; Cells; Cessation of life; Charge; Citric Acid Cycle; Cues; Cystitis; Data; Development; Drug Formulations; Electrolytes; Environment; Environmental Risk Factor; Evaluation; Frequencies; Genes; Glutamine; Gram-Negative Bacteria; Growth; Histidine; Hospitals; Image; Indwelling Catheter; Infection; Invaded; Iron; Kidney; Kidney Calculi; Knowledge; Libraries; Location; Malates; Mastigophora; Metabolism; Minority; Mirabilis; Modeling; Mus; Nitrogen; Nosocomial Infections; Nutrient; Nutritional status; Ornithine; Osmotic Pressure; Pain; Pathogenesis; Pathway interactions; Patients; Polyamines; Population; Prevention; Production; Proteus; Proteus mirabilis; Research; Role; Scientist; Severities; Severity of illness; Signal Transduction; Sodium Chloride; Source; Surface; Testing; Therapeutic; Therapeutic Intervention; Time; Urinary Calculi; Urinary tract; Urinary tract infection; Urothelial Cell; Virulence Factors; acute pyelonephritis; ascending urinary tract infection; base; catheter associated UTI; cell motility; design; fascinate; insight; migration; mutant; prevent; response; sensory mechanism; urea cycle

DESCRIPTION (provided by applicant): Catheter-associated urinary tract infection (CAUTI) is the most common hospital-acquired infection, largely due to Proteus mirabilis. This species has the unique ability to differentiate into swarm cells that migrate across catheter surfaces and gain entry to the urinary tract, where P. mirabilis can persist despite antibiotic treatment and frequently results in formation of painful urinary stones. P. mirabilis swarming is therefore a fascinating and medically-relevant problem that has perplexed scientists since its discovery. There is a fundamental gap in understanding of the specific cues and conditions that trigger P. mirabilis swarming motility, as well as the role of swarm cells during UTI. Addressing this gap has the potential to guide design of catheters or coatings that prevent entry of P. mirabilis into the urinary tract and provide new targets for disruption of persistent and severe infections, reducing the burden of CAUTI and associated complications. The central hypothesis is that Proteus mirabilis swarm cell differentiation and swarming motility are initiated in response to specific environmental cues and influence the establishment, persistence, and severity of UTI. Guided by substantial preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify specific factors and conditions that trigger swarming and determine how these factors are sensed by the bacterial population, and 2) Define the role of swarm cell differentiation and swarming triggers in the persistence and severity of UTI. Under the first aim, factors that trigger swarming by the well-characterized P. mirabilis strain HI4320 are already being identified by the candidate, based on the ability to promote swarming under normally non-permissive conditions. Media formulations in which carbon source, nitrogen source, and pH are varied are being used to determine the optimal conditions and minimal requirements for initiation of swarming motility. A transposon library has also been created and will be screened to identify mutants that have lost the ability to swarm in response to triggers, allowing for identification of genes and pathways involved in sensing and responding to the triggers. Under the second aim, the established CBA/J model of ascending UTI and biophotonic imaging will be utilized to determine the frequency and distribution of swarm cells during UTI. The contribution of swarm cells and swarming triggers to the establishment, persistence, and severity of UTI will also be addressed using the CBA/J model and mutants constructed in the first aim. The proposed research is significant because it will provide insight into how bacteria decide to perform coordinated multicellular functions, both on an agar surface and during infection of a host. This research will also contribute to a general understanding of how bacteria sense and interact with their environment, and how bacterial metabolism impacts pathogenesis. Ultimately, such knowledge has the potential to inform catheter design and therapeutic strategies for reducing the burden of CAUTI. PUBLIC HEALTH RELEVANCE: Catheter-associated urinary tract infections (CAUTI) are the most common hospital-acquired infections and are largely caused by Proteus mirabilis. Once in the urinary tract, P. mirabilis can persist despite extensive antibiotic treatment and catheter changes and frequently results in the formation of painful urinary stones, demonstrating the importance of approaches that prevent initial migration of P. mirabilis from the catheter surface to the urinary tract. Understanding the conditions that allow for migration and defining the role o this unique form of motility in the establishment, persistence, and severity of urinary tract infection has the potential to guide catheter design and provide new targets for therapeutic intervention in CAUTI.

描述（由申请人提供）：与导管相关的尿路感染（CAUTI）是最常见的医院获得的感染，主要是由于米拉比利斯的蛋白酶。该物种具有分化为跨导管表面迁移并获得的独特能力 进入尿路，尽管治疗抗生素治疗，并且经常会导致形成疼痛的尿石。因此，Mirabilis蜂拥而至是一个引人入胜且与医学相关的问题，自发现以来就一直困扰着科学家。理解触发奇怪假单胞菌蜂群运动的特定提示和条件以及群体在UTI期间的作用存在根本差距。解决这一差距的潜力可以指导导管或涂层的设计，这些导管或涂层可防止奇异假单胞菌进入尿路，并为破坏持续和严重感染的新目标提供了新的目标，从而减轻了cauti的负担和相关的并发症。中心假设是，Proteus mirabilis群体分化和蜂群的运动是根据特定的环境提示而启动的，并影响UTI的建立，持久性和严重性。在大量初步数据的指导下，该假设将通过追求两个具体目的来检验：1）确定触发群体的特定因素和条件，这些因素和条件会触发群体，并确定细菌群体如何感知这些因素，2）定义群体分化和群体群体在UTI的持久性和严重性中触发触发器的作用。在第一个目的下，基于正常非允许性的条件下促进蜂群的能力，候选人已经确定了由良好特征的Mirabilis菌株HI4320引发群体群体的因素。碳源，氮源和pH值的媒体制剂用于确定群体运动的最佳条件和最小要求。也已经创建了一个转座子库，并将筛选以识别失去对触发器群体群体的突变体，从而识别涉及传感和响应触发器的基因和途径。在第二个目标下，将利用建立的升级UTI和生物成像的CBA/J模型来确定UTI期间群体细胞的频率和分布。群体细胞和群体触发因素对UTI的建立，持久性和严重性的贡献也将使用第一个目标中的CBA/J模型和突变体来解决。拟议的研究很重要，因为它将提供有关细菌如何决定在琼脂表面和宿主感染期间执行协调多细胞功能的洞察力。这项研究还将有助于对细菌的感知和与环境相互作用以及细菌代谢如何影响发病机理的一般理解。最终，这种知识有可能为导管设计和治疗策略提供信息，从而减轻了cauti的负担。 公共卫生相关性：与导管相关的尿路感染（CAUTI）是最常见的医院获取感染，主要由Proteus mirabilis引起。一旦进入尿路，尽管广泛的抗生素治疗和导管的变化和经常导致疼痛的尿石的形成，但仍可以持续存在。了解允许迁移并定义角色的条件o在尿路感染的建立，持久性和严重性中这种独特的运动形式具有指导导管设计的潜力，并为在CAUTI的治疗干预提供了新的目标。