Monday, June 30, 2025 6/30/2025

Context-specific modulation of Clostridioides difficile virulence by Vancomycin-resistant Enterococcus faecium

Award Number: R21AI171634
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: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Context-specific modulation of Clostridioides difficile virulence by Vancomycin-resistant Enterococcus faecium - Toxin expression and sporulation by Clostridioides difficile are context-specific phenomena that integrate signals from the surrounding environment including the local nutrient milieu of the intestine. The long-term goal of this laboratory is to define the mechanistic basis of bacteria-bacteria and host interactions that modulate virulence of C. difficile. The overall objectives in this proposal are to (i) determine the mechanism of a diffusible inhibitor of C. difficile growth produced by Vancomycin-resistant Enterococcus faecium (VRE) and (ii) define the mechanism of a contact-dependent inhibition of C. difficile sporulation by VRE. The central hypothesis is that VRE modulates C. difficile virulence by multiple context-dependent mechanisms that vary depending on the available carbon source. The rationale for this project is that determination of mechanisms of interaction between the two species will allow the development of anti- VRE treatments that limit the potential for CDI. To attain the overall objectives these two specific aims will be pursued: Aim 1) Identify the mechanism of carbon source-dependent suppression of C. difficile by VRE. Based on preliminary data, the working hypothesis is: in the presence of carbon sources that are converted to organic acids by VRE, C. difficile growth is suppressed below a pH threshold and manipulation of carbon sources in vitro and in VRE colonized animals will modulate C. difficile virulence. In these experiments a defined medium will be used to screen a panel of carbon sources, enterococci, lactic acid bacteria and C.difficile strains to determine conditions modulate growth and these data will be used to develop an optimized mouse model of VRE-C. difficile infection. Aim 2) Define the contact-dependent interaction with VRE that inhibits sporulation by C. difficile. Based on preliminary data, the working hypothesis is: in the absence of a carbon source, VRE inhibits entry into sporulation by C. difficile by a non-diffusible modulator and inhibition of sporulation in this state will increase the level of toxin produced by C. difficile. In these co- culture assays and fluorescence microscopy will be used to determine if the suppression of sporulation is mediated by contact and at what developmental stage sporulation is suppressed. Genetic selection in C. difficile will be used to determine which component of the sporulation genetic program is affected by VRE. The research proposed is innovative in the applicant’s opinion because it focuses specifically on interactions between two gastrointestinal pathogens and how conditions in the gut influence the balance between virulence traits. The proposed research is significant because it will provide a context for understanding the potential for C. difficile virulence in VRE-colonized animals, which mirrors the frequent co-colonization by these two bacteria in human patients.


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: 2025 ( Subtotal = $0 )
2025	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Allergy and Infectious Diseases Research	000	2	4/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $150,160 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Allergy and Infectious Diseases Research	000	2	5/11/2023	NON-COMPETING CONTINUATION	$150,160
														Subtotal = $150,160

Issue Date FY: 2022 ( Subtotal = $150,160 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Allergy and Infectious Diseases Research	000	1	5/26/2022	NEW	$150,160
														Subtotal = $150,160

Grand Total All Awards = $300,320

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Context-specific modulation of Clostridioides difficile virulence by Vancomycin-resistant Enterococcus faecium

Award Number: R21AI171634

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: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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