Dynamics of Pseudomonas aeruginosa During Bacteremia

菌血症期间铜绿假单胞菌的动态

• 批准号: 10042352
• 负责人: ALAN R HAUSER
• 金额: $ 23.7万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-24 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042352
• 关键词: Address; Amplifiers; Antibiotics; Area; Back; Bacteremia; Bacteria; Bar Codes; Blood; Blood Circulation; Cavia; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Cholecystectomy; Common bile duct structure; Disease; Etiology; Feedback; Foundations; Frequencies; Gallbladder; Gastrointestinal tract structure; Human; Infection; Intervention; Intestines; Keratitis; Knowledge; Libraries; Light; Liver; Lung; Modeling; Mus; Mutation; Nosocomial Infections; Oral Administration; Organ; Outcome; Pathogenesis; Pathogenicity; Pneumonia; Population; Prevalence; Process; Pseudomonas aeruginosa; Reporting; Resistance to infection; Seeds; Sepsis; Severities; Severity of illness; Source; Spleen; Tail; Testing; Therapeutic Agents; Veins; attributable mortality; experimental study; fitness; gastrointestinal; gastrointestinal bacteria; genome sequencing; improved outcome; mortality; mouse model; multidrug-resistant Pseudomonas aeruginosa; novel; novel therapeutic intervention; novel therapeutics; public health priorities; resistant strain; whole genome

Pseudomonas aeruginosa (PA) is the third most common gram-negative etiology of bloodstream infections, and these infections are associated with a crude mortality rate of 39%. Despite their frequency and severity, PA bloodstream infections are relatively poorly understood compared to pneumonia, burn infections, and keratitis. To investigate the pathogenesis of PA bloodstream infections, we have used a mouse model in which the tail vein is injected with a library of barcoded bacteria. Our preliminary experiments yielded several unexpected findings. First, in approximately half of severely ill bacteremic mice, the PA bacteria found disseminated throughout the body were descendants of just a few bacterial cells, suggesting that only a small number of the PA in the initial inoculum persisted and disseminated to cause severe disease. Second, PA bacteria in the blood migrated through a tight bottleneck to the gallbladder, which was a protective niche that allowed for a small number of PA to replicate to extremely high numbers. From there, these descendants of just a few PA bacteria seeded the intestines, presumably by passing through the common bile duct. This finding is particularly interesting in the context of other reports suggesting that PA is capable of migrating from the intestines to the bloodstream. Together, these observations suggest the intriguing hypothesis that spread of PA from the bloodstream to the intestines and back to the bloodstream may generate a "positive feedback loop" in which the gallbladder serves as an amplifier of PA numbers. In this application, we propose to address this limitation and directly test our hypothesis by performing the following specific aims: (1) Characterize bacterial dynamics over the course of PA bloodstream infections. (2) Determine whether interventions that disrupt PA transit through the intestines improve outcomes in bloodstream infections. Completion of these aims has the potential to uncover novel pathogenic mechanisms that contribute to the poor outcomes observed in PA bloodstream infections. The impact of these studies is three-fold: (i) they may provide a rationale for examining the pathogenesis of bloodstream infections caused by bacteria other than PA; (ii) the knowledge gained may be used as a foundation and justification for costlier and more laborious studies in humans with PA bloodstream infections; and (iii) these studies may inform novel therapeutic interventions that lower the unacceptably high mortality rates currently associated with PA bacteremia.

铜绿假单胞菌(PA)是血液感染的第三大革兰氏阴性病原菌， 这些感染与39%的粗死亡率有关。尽管它们的频率和严重性， 与肺炎、烧伤感染相比，人们对PA血液感染的了解相对较少 角膜炎。为了研究PA血流感染的发病机制，我们使用了一种小鼠模型，在该模型中 尾静脉被注射了条形码细菌库。我们的初步实验产生了几个 意想不到的发现。首先，在大约一半的严重菌血症小鼠中，PA细菌发现 散布在全身的只有几个细菌细胞的后代，这表明只有一小部分 初始接种中的PA数量持续并传播，导致严重的疾病。第二，宾夕法尼亚州 血液中的细菌通过一个紧密的瓶颈迁移到胆囊部，这是一个保护性的利基环境 允许少量的PA复制到极高的数量。从那里，这些人的后代 据推测，只有少数PA细菌通过胆总管在肠道播种。这 这一发现在其他报告的背景下特别有趣，这些报告表明PA能够从 从肠道到血液。总而言之，这些观察表明了一个有趣的假设，即 PA从血流到肠道，再回到血流的过程可能会产生“正反馈” 在这一应用中，我们建议解决 通过执行以下具体目标来直接检验我们的假设：(1)表征 PA血流感染过程中的细菌动态。(2)确定干预措施是否 扰乱PA在肠道中的转运可以改善血液感染的预后。完成 有可能发现导致不良结局的新的致病机制 在PA血流感染中观察到。这些研究的影响有三个方面：(I)它们可能提供 研究由PA以外的细菌引起的血液感染的发病机制；(Ii) 所获得的知识可以作为更昂贵、更费力的研究的基础和理由 和(Iii)这些研究可能为新的治疗干预措施提供信息， 降低目前与PA菌血症相关的不可接受的高死亡率。