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Dynamics of Pseudomonas aeruginosa During Bacteremia

菌血症期间铜绿假单胞菌的动态

基本信息

批准号：
10222524
负责人：
ALAN R HAUSER
金额：
$ 19.75万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-24 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222524
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 porcine model public health priorities resistant strain whole genome

项目摘要

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，

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Forest and Trees: Exploring Bacterial Virulence with Genome-wide Association Studies and Machine Learning.

DOI：
10.1016/j.tim.2020.12.002
发表时间：
2021-07
期刊：
Trends in microbiology
影响因子：
15.9
作者：
Allen JP;Snitkin E;Pincus NB;Hauser AR
通讯作者：
Hauser AR

Taxonomic characterization of Pseudomonas hygromyciniae sp. nov., a novel species discovered from a commercially purchased antibiotic.

DOI：
10.1128/spectrum.01838-21
发表时间：
2023-09-22
期刊：
MICROBIOLOGY SPECTRUM
影响因子：
3.7
作者：
Turner, Timothy L.;Mitra, Sumitra D.;Kochan, Travis J.;Pincus, Nathan B.;Lebrun-Corbin, Marine;Cheung, Bettina H.;Gatesy, Samuel W.;Afzal, Tania;Nozick, Sophie H.;Ozer, Egon A.;Hauser, Alan R.
通讯作者：
Hauser, Alan R.

Genomics of Aminoglycoside Resistance in Pseudomonas aeruginosa Bloodstream Infections at a United States Academic Hospital.

美国学术医院铜绿假单胞菌血流感染的氨基糖苷耐药性基因组学。