Wednesday, March 22, 2023
3/22/2023
PROJECT SUMMARY Significance: Urinary tract infections (UTIs) are the most common adult bacterial infection annually affecting over 150 million individuals worldwide. As a common reason for antibiotic prescriptions, UTIs are considered a substantial source of resistance to antimicrobial agents. Thus, improved understanding of the interactions between host and bacterial pathogen during UTI is essential for facilitating the development of new therapeutic agents. The concentration of copper increases 5-fold in the urine during acute infection as a protective strategy against the pathogen. Most copper is excreted in the intestines where uropathogens colonize following UTI forming the basis for recurrent infections. Uropathogenic Escherichia coli (UPEC), the most common cause of UTIs, uses copper efflux and sequestration mechanisms to prevent copper toxicity. Additionally, UPEC inhabits multiple niches (intestines, vagina, and bladder) throughout the host that vary in copper content and oxygen concentration. While copper response mechanisms have been characterized in laboratory strains of E. coli, the relative contribution of each copper response system to UPEC persistence in the host has not been elucidated. This proposal will determine the spatio-temporal induction and regulation of the UPEC response to copper and will define the role of each response system in mediating UPEC persistence in the host. Rationale and Hypothesis: In order to successfully infect the urinary tract, UPEC must tolerate increased copper levels. Similarly, UPEC must tolerate intestinal copper excretion to colonize the host gut and potentially cause re-infections. Based on prior studies, the copper responsive UPEC locus cus is among the most upregulated of all genes in samples from acute human UTIs. The cus locus encodes the two-component signaling system CusSR, a copper sensing and response signaling system, and copper efflux apparatus CusCFBA. Additionally, the copper response systems CueR/CopA facilitate copper export in aerobic conditions. Oxygen availability is a key determinant of which copper response system is preferentially active in E. coli due to the oxidation state of copper and energetic requirements for copper efflux. Oxygen levels vary widely within UPEC’s niches. I hypothesize that oxygen availability and copper levels dictate the copper response systems that are active in the anatomic niches that UPEC colonizes and infects. I propose two aims to test this hypothesis: Aims: Aim 1 will determine which UPEC copper response systems are active in the anatomic niches (vagina, intestines, bladder) that UPEC encounters. Aim 2 will investigate the role of CusSR in mediating copper sensing and tolerance in the anaerobic intestinal niche. Impact: These studies will be the first to address the hierarchy and localization of copper response systems uropathogenesis. Clarification of how UPEC senses and responds to copper will provide insight into whether targeting copper detoxification methods of UPEC is a viable therapeutic option for UTI treatment and prevention.
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