Copper at Host-Pathogen Interface During Urinary Tract Infection

About This Grant

PROJECT SUMMARY: Bacterial infection in the urinary bladder is one of the most common infectious conditions in humans. The predominant etiological agent of urinary tract infection (UTI) is uropathogenic Escherichia coli (UPEC). Antimicrobial resistance in UPEC and other uropathogens is increasing at an alarming rate globally. Therefore, there is an immediate need for development of novel strategies to manage UTI. We have demonstrated that copper (Cu) is mobilized to the urine as a host response during clinical UTI in patients. Cu is a protective effector of nutritional immunity against uropathogens in the mouse and non-human primate models of UTI. Collectively, multiple lines of evidence support a novel biological role for Cu during UTI. This proposal addresses the important gaps in knowledge to harness the protective role of Cu to resolve UTI. The proposed research is significant because our findings are anticipated to break new ground to develop a host effector-dependent solution to combat UTI. Our approach is innovative because we seek to define and augment the protective role of an endogenous host effector to resolve UTI. Major objectives of this proposal are to define the role of Cu homeostasis mechanisms in UPEC virulence, to investigate the contribution of ceruloplasmin in protection against UTI, and to determine the impact of novel Cu-dependent antimicrobials on resolving UTI in the mouse model. Based on our published and preliminary data, we hypothesize that Cu homeostasis in the pathogen and the host determines the outcome of UTI, and that Cu-dependent antimicrobials will promote uropathogen clearance during UTI. The rationale for this study is that understanding the impact of Cu homeostasis in the pathogen and host is critical to develop and evaluate therapeutics that bolster nutritional immunity to resolve UTI. This central hypothesis will be tested with specific aims: 1) Determine copper homeostatic mechanisms in UPEC and their impact on host-pathogen interaction during UTI; 2) Define the role of ceruloplasmin in protection from bacterial pathogens in the urinary tract; and 3) Evaluate novel copper-dependent antimicrobials on pathogen clearance in a mouse model of UTI. The expected outcomes of this study include elucidating Cu homeostatic mechanisms in UPEC, defining virulence of uropathogens in mammalian hosts lacking ceruloplasmin, and assessing novel Cu-dependent antimicrobials against uropathogens in the mouse model of UTI. The substantial positive impact of this study will be advanced understanding of an effector of nutritional immunity during UTI and translating this knowledge to assess its therapeutic potential against UTI. In summary, the proposed study is expected to confer a significant public health benefit against UTI, an extremely common and profoundly painful infectious condition affecting tens of millions of people globally whose clinical management is increasingly challenged by ever rising antimicrobial resistance.