Evolution of Pseudomonas aeruginosa in premise plumbing and impact on cystic fibrosis respiratory disease pathogenesis - Potable water is a major source of opportunistic pathogens that cause a variety of life-threatening infections in immunocompromised people, with a yearly US economic burden of $2.4 billion dollars. Biofilms ubiquitously coat surfaces within building premise plumbing that delivers potable water (e.g. water pipes, faucets, shower heads) and serve as a reservoir for opportunistic pathogens, including Pseudomonas aeruginosa. My postdoctoral studies and work from other laboratories implicate potable water as a source of P. aeruginosa that causes deadly respiratory infections in people with cystic fibrosis (CF). While P. aeruginosa persists in premise plumbing biofilms for months or years prior to infection, it is unknown how evolution in this niche impacts its pathogenic potential. The success of P. aeruginosa as a CF pathogen is owed in part to how it adaptively evolves in response to selective pressures in the airways, including nutrient limitation, antimicrobials, phagocytosis by immune cells, and microbiota interactions. Selective pressures in plumbing resemble those in the airways, including scarce nutrients, residual disinfectant (e.g. monochloramine), phagocytosis by amoebae, and polymicrobial competition. Preliminary data suggests evolution in plumbing impacts traits associated with infection of CF airways. The long- term goal of the candidate, Dr. Catherine Armbruster, is to establish an independent research program focused on how evolution of opportunistic pathogens in response to selective pressures faced in plumbing biofilms impacts downstream pathogenesis at different sites of infection. To achieve this goal, the immediate career objective of Dr. Armbruster is to obtain an independent faculty position using research proposed in this application as the foundation of her job applications. The overall research objective is to understand how evolution in response to selective pressures in plumbing biofilms impacts colonization and persistence in CF airways. The hypothesis is that low nutrients, polymicrobial competition, and exposure to monochloramine in plumbing biofilms select for P. aeruginosa traits that promote biofilm formation, protection from antimicrobials and immune responses, and increase competitiveness against microbes in CF airways. To test this hypothesis, two specific aims are proposed. The first aim identifies key P. aeruginosa pathways for survival in plumbing and how they evolve in response to specific pressures applied in a potable water biofilm model system. The second aim defines the subset of these adaptations that enhance fitness during host-pathogen interactions, using CF as a model system. These aims are expected to demonstrate how opportunistic pathogens are shaped by specific ecological and evolutionary factors prior to infection that impact downstream host-pathogen interactions. Successful completion of these aims will provide preliminary data for a competitive R01 application within two years of this award. Finally, proposed career development activities will complement Dr. Armbruster’s prior training. Dr. Bomberger, the postdoctoral advisor to Dr. Armbruster, is included as a scientific advisor because she is a leader in CF research with a strong track record of training successful independent academic scientists.
