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) 是血流感染的第三大常见革兰氏阴性病因， 这些感染的粗死亡率为 39%。尽管它们的频率和严重性， 与肺炎、烧伤感染和肺炎相比，人们对 PA 血流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，我们使用了小鼠模型，其中 尾静脉注射了带有条形码的细菌文库。我们的初步实验取得了一些成果 意想不到的发现。首先，在大约一半的严重菌血症小鼠中，发现 PA 细菌 散布在全身的只是少数细菌细胞的后代，这表明只有一小部分细菌细胞 初始接种物中的 PA 数量持续存在并传播，导致严重疾病。二、PA 血液中的细菌通过一个紧密的瓶颈迁移到胆囊，这是一个保护性生态位， 允许少量的 PA 复制到极高的数量。从那里开始，这些后代 只有少数 PA 细菌在肠道中播种，大概是通过胆总管传播的。这 与其他表明 PA 能够从 肠道进入血液。这些观察结果共同提出了一个有趣的假设： PA从血流到肠道再回到血流可能会产生“正反馈” 循环”，其中胆囊充当 PA 数字的放大器。在本应用中，我们建议解决 克服这一限制，并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) 确定是否进行干预 扰乱 PA 通过肠道的转运可改善血流感染的结果。完成 这些目标中有可能发现导致不良结果的新致病机制 在 PA 血流感染中观察到。这些研究的影响有三重：(i) 它们可能提供 检查 PA 以外的细菌引起的血流感染发病机制的基本原理； (二) 所获得的知识可以用作更昂贵和更费力的研究的基础和理由 患有 PA 血流感染的人； (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 菌血症相关的令人难以接受的高死亡率。