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

项目摘要和摘要 高达20%的鲍曼不动杆菌(Ab)临床分离株来自尿路来源， 这些泌尿系病例中有很大一部分是在医院外发病的。我区40%-60%的尿路分离株 是多药耐药(MDR)，表明抗体是如何导致日益增长的多药耐药流行的 (MDR)尿路感染(UTI)。尽管对新的、省去抗生素的抗体干预措施的需求 UTIs、介导致尿路感染鲍曼不动杆菌毒力的微生物因素和影响UPAb毒力的宿主因素 对UPAb感染的易感性仍不明确。我们最近证明了抗体株在它们的 在小鼠尿路感染模型中定植尿路的能力。此外，我们还鉴定了微生物成分 增加抗体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，我们发现抗体尿液和呼吸道病例表现出分化 临床和微生物学特征。总而言之，这些发现强烈暗示UPAb 包括一种抗体亚群，与引起其他疾病的抗体相比，该抗体亚群具有独特的感染尿路的能力 感染的类型。 这项建议解决了理解抗体流行病学和病理生物学的基本点，其中包括 对抗体尿毒力的特别关注： 1)uPAb是临床相关抗体的一个可区分的亚群吗？ 2)弓形虫感染与其他类型的抗体感染的宿主易感因素是否不同？对战 尿路感染是由其他更常见的泌尿系统病原体(如肠杆菌科或假单胞菌)引起的？ 3)降低UPAb在尿液中的固有生存能力能否成为抑制其尿毒力的一种策略？ 利用丹塔斯实验室开发的比较基因组分析管道，我将研究微生物 与不动杆菌临床分离株匹配的大量不动杆菌中泌尿系疾病的分子决定因素 各自的临床资料。我还将在一篇发表的回顾文章中确定与AbUTI相关的宿主特征 在我们的医疗保健系统中有2000多例抗体病例。最后，利用分子技术和小鼠尿路感染 在费尔德曼实验室开发的模型中，我将调查UPAb株与 在人类尿液中生长，以及它感染小鼠尿路的能力。这将评估体外尿液 生长模型可以有效地用于筛选多药耐药抗体UTI的治疗靶点。通过成功 完成本研究，接受教学培训，并接受多学科的指导 专家指导委员会，我的目标是开始我的职业生涯，作为一名独立的翻译研究员 研究被忽视的不动杆菌病发病的宿主和微生物决定因素。

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.