Defining microbial and host determinants of Acinetobacter survival in the urinary tract

项目概要和摘要 高达20%的鲍曼不动杆菌（Ab）临床分离株来自尿源， 这些泌尿系统疾病大部分都是在医院外发病的。本地区40 - 60%的尿分离株 多药耐药（MDR），表明抗体如何有助于多药耐药的日益流行， (MDR)尿路感染（UTIs）。尽管需要新的、不损害免疫力的抗Ab干预措施， UTIs是介导尿路致病性A.鲍曼不动杆菌（UPAb）毒力和宿主因子， 易患UPAb感染，仍然定义不清。我们最近证明，抗体株在其 在鼠UTI模型中定殖泌尿道的能力。此外，我们还发现了 增加Ab菌株感染膀胱的能力，但不会增加其在呼吸道感染中的毒力。 最后，在最近的一项流行病学研究中，我们发现泌尿系和呼吸道的Ab病例表现出不同的趋势， 临床和微生物学特征。总之，这些发现强烈提示UPAb 包括与引起其它尿路感染的Ab相比， 感染的类型。 该提案涉及理解Ab流行病学和病理生物学的基本要点， 特别关注Ab尿毒力： 1)UPAb是否为临床相关Ab的可区分亚群？ 2)Ab UTI与其他类型的Ab感染之间的宿主易感因素是否不同？与 由其他更常见的泌尿病原体引起的UTI（即，肠杆菌科或假单胞菌属）？ 3)降低UPAb在尿液中生存的内在能力是否可以成为抑制其尿毒力的策略？ 使用Dantas实验室开发的比较基因组分析管道，我将研究微生物 在一个大型的不动杆菌临床分离株库中， 各自的临床数据。我还将在已发表的回顾性研究中确定与Ab UTI相关的宿主特征 我们的医疗系统中有超过2000例Ab病例。最后，采用分子技术和小鼠UTI， 在费尔德曼实验室开发的模型，我将调查UPAb菌株的能力之间的潜在联系， 在人类尿液中生长，并能感染鼠类泌尿道。这将评估体外尿液是否 生长模型可有效地用于筛选MDRAbUTI治疗靶点。通过成功 完成这项研究，接受教学培训，并接受多学科的指导 我的目标是作为一名独立的翻译研究人员开始我的职业生涯 调查宿主和微生物在被忽视的不动杆菌病中致病的决定因素。

Project Summary and Abstract Up to 20% of all Acinetobacter baumannii (Ab) clinical isolates are obtained from urinary sources, and a large portion of these urinary cases have their onset outside of hospitals. 40-60% of urinary isolates in our region are multidrug resistant (MDR), demonstrating how Ab contributes to the growing epidemic of multidrug resistant (MDR) urinary tract infections (UTIs). Despite the demand for novel, antibiotic-sparing interventions against Ab UTIs, the microbial factors that mediate uropathogenic A. baumannii (UPAb) virulence and the host factors that predispose to UPAb infections, remain poorly defined. We recently demonstrated that Ab strains vary in their ability to colonize the urinary tract in a murine UTI model. Additionally, we identified microbial elements that increase an Ab strain’s ability to infect bladders but do not contribute to its virulence in respiratory infections. Lastly, in a recent epidemiological study, we found that Ab urinary and respiratory cases exhibited diverging clinical and microbiological characteristics. Altogether, these findings are strongly suggestive that UPAb comprise an Ab subpopulation distinctively equipped to infect urinary tracts, compared to Ab that cause other types of infections. This proposal addresses fundamental points in understanding Ab epidemiology and pathobiology, with a specific focus on Ab urovirulence: 1) Are UPAb a distinguishable subpopulation of clinically-relevant Ab? 2) Do host predisposing factors differ between Ab UTI versus other types of Ab infections? Versus UTI caused by other, more common uropathogens (i.e., Enterobacteriaceae or Pseudomonas)? 3) Can reducing UPAb’s intrinsic ability to survive in urine be a strategy to curb its urovirulence? Using comparative genomic analysis pipelines developed in the Dantas Lab, I will investigate microbial molecular determinants of urinary disease in a large bank of Acinetobacter clinical isolates matched to their respective clinical data. I will also identify host characteristics associated with Ab UTI in a published retrospective cohort of over 2000 Ab cases in our healthcare system. Lastly, employing molecular techniques and murine UTI models developed in the Feldman lab, I will investigate the prospective link between a UPAb strain’s ability to grow in human urine, and its ability to infect the murine urinary tract. This will evaluate whether in vitro urine growth models can be effectively employed to screen for MDR Ab UTI therapeutic targets. Through successful completion of this research, undergoing the didactic training, and receiving guidance from a multidisciplinary mentoring committee of experts, I aim to launch my career as an independent translational researcher investigating the host and microbial determinants of pathogenesis in neglected forms of Acinetobacter disease.