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常见革兰氏阴性病因， 这些感染与39％的原油死亡率有关。尽管它们的频率和严重程度 与肺炎，烧伤感染和 角膜炎。为了研究PA血液感染的发病机理，我们使用了小鼠模型 尾静脉注射了一个条形码细菌库。我们的初步实验产生了几个 意外的发现。首先，在大约一半的严重疾病的细菌小鼠中，发现PA细菌 在整个体内传播的是只有几个细菌细胞的后代，这表明只有一个小 初始接种物中的PA数量持续并散布以引起严重疾病。第二，宾夕法尼亚州 血液中的细菌通过紧密的瓶颈迁移到胆囊，这是一个保护性的生态裂市场 允许少数PA复制到极高的数字。从那里，这些后代 只有几种PA细菌将肠子播种，大概是通过普通的胆管。这 在其他报告的背景下，发现尤其有趣，表明PA能够从 肠子到血液。总之，这些观察结果表明了一个有趣的假设，即传播 从血液到肠道再回到血液的PA可能会产生“积极的反馈” 循环“胆囊用作PA数字的放大器。在此应用程序中，我们建议解决 此限制并通过执行以下特定目的直接检验我们的假设：（1）表征 PA血液感染过程中的细菌动力学。 （2）确定是否干预 通过肠道破坏PA的过渡会改善血液感染的预后。完成 这些目标有可能发现新颖的病原机制，从而导致不良结果 在PA血液感染中观察到。这些研究的影响是三个方面：（i）它们可能会提供 研究由PA以外的细菌引起的血液感染的发病机理的理由； （ii） 获得的知识可能被用作成本和更费力的研究的基础和理由 患有PA血液感染的人； （iii）这些研究可能会为新颖的治疗干预措施提供信息 降低目前与PA菌血症相关的高死亡率。