HARNESSING COPPER TO IMPEDE UROPATHOGEN COLONIZATION

Urinary tract infection (UTI) is one of the most common bacterial infections encountered by humans.Uropathogenic Escherichia coli (UPEC), Klebsiella pneumoniae and Proteus mirabilis are the predominantetiological agents of UTI. Women, children, and the elderly are highly susceptible to UTI. Meteoric increase inantibiotic resistance rates in uropathogens raises an urgent need for the development of novel strategies tomanage UTI. Our work has demonstrated that copper is mobilized to urine as a host response during clinicalUTI in patients and is involved in protection against UTI in the mouse model. Our findings and reports of fatalcomplications of UTI in patients with Menkes disease (who cannot absorb dietary copper), highlight a novelbiological role for copper in the protection against UTI. Our long-term research goal is to define the molecularand cellular features of host-pathogen interaction during UTI to identify targets for therapeutic development.The major objective of this proposal is to determine the impact of endogenous and increased urinary copper onbacterial colonization during UTI. Based on our published and preliminary data, we hypothesize that host-derived copper is involved in protection against uropathogen colonization and increasing urinarycopper content will promote bacterial clearance during UTI. The rationale for this study is thatunderstanding the protective role of copper on bacterial colonization during UTI is critical to developtherapeutics that bolster this innate response to resolve UTI. Utilizing a mouse model of UTI, clinical isolates ofUPEC, K. pneumoniae and P. mirabilis, and isogenic bacterial mutants lacking copper-efflux pumps, we willtest our central hypothesis by pursuing the following Specific Aims: 1) Determine the impact of endogenous,host-derived copper on deterring bacterial colonization during UTI; and 2) Determine the effect of increasedurinary copper level on bacterial clearance from the urinary tract. The expected outcome of this study is tounderstand the impact of endogenous copper on clearance of clinically significant uropathogens from theurinary tract during UTI. Increased urinary copper content is anticipated to promote bacterial clearance in themouse model of UTI. The substantial positive impact of this study will be elucidating the role of an innate hostdefense effector in protection against UTI by major uropathogens. The proposed research is significantbecause our findings are anticipated to break new ground to develop novel interventions against UTI. Ourapproach is innovative because we seek to bolster a host effector that is amenable to modulation by dietaryand pharmacological intervention to promote resolution of UTI. In summary, the proposed study is expected toconfer a significant public health benefit against UTI, a ubiquitous and profoundly painful infectious diseaseaffecting millions of people.