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Unraveling the Functional Redundancy and Activation Mechanisms of Enterococcal Proteases in Catheter-Associated Urinary Tract Infections (CAUTI)

Award Number: R21AI195633
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Unraveling the Functional Redundancy and Activation Mechanisms of Enterococcal Proteases in Catheter-Associated Urinary Tract Infections (CAUTI) - Project Summary/Abstract Catheter-associated urinary tract infections (CAUTIs) caused by Enterococcus faecalis are a pervasive clinical challenge, characterized by high rates of antibiotic resistance and recurrence due to biofilm formation. The secreted metalloprotease GelE and serine protease SprE are master regulators of E. faecalis virulence, critical for biofilm maturation and tissue invasion. Canonical models dictate that SprE requires proteolytic activation by GelE. However, our published work reveals a paradox: SprE retains significant proteolytic activity in urine even in the absence of GelE, suggesting an alternative, host-dependent activation mechanism. Our central hypothesis is that the urinary tract microenvironment activates SprE via host proteases (e.g., trypsin), enabling synergistic GelE/SprE function in fibrinogen cleavage and biofilm stabilization to drive CAUTI persistence. This hypothesis will be tested through two synergistic specific aims. In Aim 1, we will define the urinary tract-specific regulatory and activation mechanisms of GelE and SprE. Using in vivo immunoprecipitation and LC-MS/MS, we will map host protease-mediated cleavage sites on SprE from catheter biofilms. Concurrently, RNA-seq will be used to define how host fibrinogen reprograms the Fsr quorum- sensing circuit to upregulate protease expression. In Aim 2, we will dissect how GelE and SprE exploit host fibrinogen to drive biofilm architecture and tissue invasion. Using our robust murine CAUTI model and confocal microscopy, we will quantify fibrinogen-dependent biofilm formation on explanted catheters. Furthermore, we will map protease-mediated epithelial disruption by analyzing bacterial invasion, junctional integrity (E-cadherin), and host cell death in bladder tissues. The proposed research is significant because it challenges the existing paradigm of autonomous bacterial protease regulation by introducing a novel host-to-pathogen signaling mechanism. By defining the trypsin-SprE interface and the fibrinogen-protease-biofilm axis, this work will identify new diagnostic biomarkers (e.g., urinary E-cadherin fragments) and therapeutic targets for novel catheter coatings or anti-virulence agents. This is particularly relevant for states like West Virginia, where comorbidities such as diabetes elevate fibrinogen levels and exacerbate CAUTI severity amidst a rising antimicrobial resistance crisis.


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 = $221,250 )
2026	2026	MARSHALL UNIVERSITY RESEARCH CORPORATION	1 JOHN MARSHALL DR	HUNTINGTON	WV	25755	CABELL	USA	Allergy and Infectious Diseases Research	000	1	7/3/2026	NEW	$221,250
														Subtotal = $221,250

Grand Total All Awards = $221,250

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Unraveling the Functional Redundancy and Activation Mechanisms of Enterococcal Proteases in Catheter-Associated Urinary Tract Infections (CAUTI)

Award Number: R21AI195633

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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