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Copper Sensing in Uropathogenic Escherichia coli

Award Number: F30AI169748
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Copper Sensing in Uropathogenic Escherichia coli - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $54,538 )
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	4	12/29/2025	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $54,538

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	3	8/8/2025	NON-COMPETING CONTINUATION	$564
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	3	12/23/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $34,229 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	2	5/9/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	2	1/29/2024	NON-COMPETING CONTINUATION	$32,949
														Subtotal = $34,229

Issue Date FY: 2023 ( Subtotal = $32,949 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Allergy and Infectious Diseases Research	002	1	1/30/2023	NEW	$0
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Allergy and Infectious Diseases Research	003	1	2/21/2023	NEW	$942
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	1	1/11/2023	NEW	$0
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	1	12/19/2022	NEW	$32,007
														Subtotal = $32,949

Grand Total All Awards = $176,254

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Copper Sensing in Uropathogenic Escherichia coli

Award Number: F30AI169748

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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