Copper is a Host Effector in Protection Against Urinary Tract Infection
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The urinary tract, especially the bladder, is one of the most common sites of bacterial infection inhumans. Uropathogenic Escherichia coli (UPEC) is the predominant cause of urinary tract infection (UTI).Women, children, the elderly, and individuals with catheters, uroliths, or diabetes mellitus are highlysusceptible to UTI. There is an immediate need for novel strategies to manage UTI because of an alarmingincrease in antibiotic resistance in UPEC globally. We have demonstrated that copper (Cu) is mobilized tourine as a host response during clinical UTI in patients. We have developed a non-human primate model ofUTI that recapitulates urinary Cu mobilization observed in human UTI. Our findings, taken together with reportsof fulminant UTI in patients with Menkes disease (who cannot absorb dietary Cu), highlight an important andnovel biological role for Cu 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.Major objectives of this proposal are to define the mechanism of Cu-mediated protection against UPECcolonization, and to determine how Cu is mobilized to urine during UTI. Based on our published andpreliminary data, we hypothesize that Cu is mobilized to urine in response to UPEC signals to impedebacterial survival, and that augmenting the toxicity of Cu will promote UPEC clearance. The rationale forthe proposed work is that understanding Cu mobilization, and its impact on UPEC survival are critical todevelop therapeutics that bolster this innate response to resolve UTI. We will test our central hypothesis bypursuing the following specific aims: 1) Determine how copper deters UPEC survival, and identify pathogensignals that trigger copper mobilization; 2) Define the mechanism of copper-mediated UPEC killing withinhuman phagocytes; and 3) Determine the effect of augmenting the toxicity of copper on UPEC clearance. Theexpected outcomes of this study include understanding the direct and indirect impact of Cu on UPECclearance during UTI, and the identification of the pathogen signals that trigger Cu mobilization. We willdetermine the mechanism of Cu-mediated UPEC killing in human phagocytes. Cu-boosting treatments areanticipated to promote UPEC clearance in the mouse and non-human primate models of UTI. The substantialpositive impact of this study will be elucidating the role of an innate host defense effector in protection againstUTI in humans. The proposed research is significant because our findings are anticipated to break new groundto develop novel interventions against UTI. Our approach is innovative because we seek to bolster a hosteffector that is amenable to dietary and pharmacological modulation, to promote resolution of UTI. In summary,the proposed study is expected to confer a significant public health benefit against UTI, a ubiquitous andprofoundly painful infectious disease affecting millions of people.