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

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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.