Identifying niche specific adaptations in Acinetobacter baumannii

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Abstract Acinetobacter baumannii (Ab), the most clinically relevant member of the Acinetobacter genus, is an opportunistic pathogen. This bacterium has an alarming predisposition to acquire multi-drug resistance (MDR), and infections associated with MDR-Ab strains are linked to greater morbidity and mortality. Accordingly, carbapenem-resistant Ab recently topped the WHO priority list of bacteria that require research and development of novel therapeutic strategies. Despite the significant worldwide impact of MDR-Ab, when compared to other major MDR pathogens, relatively little is known about Ab pathogenesis. Although Ab most commonly causes pneumonia (40 % of cases), no lung isolates have been used to study Ab pneumonia in animal infection models. Ab also commonly infects other niches such as blood, the urinary tract, and soft-tissues. Classically, Ab strains are regarded as a homogenous group of opportunistic pathogens displaying niche-indiscriminate virulence in critically-ill hosts. As a result, Ab research efforts often extrapolate findings from one Ab strain in a single model of infection to draw conclusions about Ab as a whole. Recent data from my lab has challenged the concept that Ab lacks niche-specificity. Our retrospective analysis indicated that ~20% of Ab clinical isolates are obtained from urinary sources, often from patients with indwelling catheters. Despite this relevant statistic, research on Ab pathogenesis in the context of catheter-associated urinary tract infection (CAUTI) was nonexistent. Thus, my group established the first murine model of Ab CAUTI and employed it to characterize UPAB1, a recent MDR urinary isolate. Employing this model, we have collected evidence that there are genetic determinants in Ab that influence both niche specificity and the infection outcome. In preliminary experiments, we have infected mice with Ab strains from urinary and respiratory sources and identified strains that perform well in one infection model, but poorly in the other. We hypothesize that genetically determined, niche-specific adaptations have occurred in modern Ab strains. In this proposal we will classify Ab strains in niche-specific or generalist groups. Employing comparative genomics, we will determine the genetic elements responsible for niche-specific adaptations and virulence. We expect to identify niche-specific virulence determinants that may be novel targets for innovative antibiotic-independent therapies. Furthermore, the genetic and phenotypic markers identified in this study could help inform the best triage practices and therapeutic interventions to combat potential Ab outbreaks. Finally, we expect to identify modern uropathogenic and respiratory Ab strains that can be broadly adopted by the research community to better investigate two leading manifestations of Ab disease.