Wednesday, April 2, 2025
4/2/2025
Elucidating regulatory control of Acinetobacter baumannii persistence and spread - SUMMARY Acinetobacter baumannii is an emerging nosocomial pathogen and a leading global cause of ventilator- associated pneumonia. This pathogen also infects a number of other anatomical sites, resulting in wound, urinary tract, and bloodstream infections, meningitis, and endocarditis. A. baumannii infections are extremely recalcitrant to therapeutic interventions, largely due to the acquisition of antibiotic resistance by this pathogen. Nosocomial transmissions of A. baumannii frequently occur in critically ill hospital patients, typically following contact with contaminated hospital surfaces, personnel, or medical devices. Bacteria persisting on hospital surfaces must tolerate an onslaught of environmental stresses, principal among them being the loss of water, or desiccation. A. baumannii is extremely desiccation tolerant and this phenotype is observed across a wide spectrum of clinical and laboratory isolates, suggesting that genes promoting desiccation tolerance are broadly conserved in this pathogen. However, the factors promoting desiccation tolerance in A. baumannii remain largely undefined. Additionally, it is well established that exposure to environmental stresses modulates the virulence of A. baumannii; however, the impact that persistence in a desiccated state has on the transmission and virulence of A. baumannii has not been explored. In preliminary experiments, we have discovered that Lon protease serves as a critical regulator of the A. baumannii response to desiccation and we have determined that Lon regulates the expression of a highly disordered protein, DtpA, which is required for the extreme desiccation tolerance of this organism. Additionally, we have found that desiccated A. baumannii causes more virulent disease in a murine model of pneumonia, suggesting that factors required to tolerate desiccation may promote pathogenesis within the mammalian host. Here, we propose to determine the molecular mechanisms underlying these phenotypes and reveal the mechanisms linking environmental persistence and pathogenicity in A. baumannii by 1) defining the mechanism of Lon protease-mediated regulation of dtpA transcription, 2) elucidating the regulation and function of Lon protease in response to desiccation, and 3) interrogating the molecular link between A. baumannii desiccation tolerance and virulence. Together, these studies will improve our understanding of how A. baumannii persists in the environment and define the impact that environmental persistence has on the transmission of this emerging pathogen. Additionally, findings from this work may be applied to the study of other nosocomial pathogens to more broadly understand how bacterial transmission occurs in hospital settings.
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