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Toxin B receptor mediated events in Clostridioides difficile disease

Award Number: F31AI179208
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/05/2024
PERIOD OF PERFORMANCE END DATE: 05/09/2025

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Toxin B receptor mediated events in Clostridioides difficile disease - PROJECT SUMMARY Clostridioides difficile is a toxigenic, anaerobic bacterium that is a leading cause of antibiotic associated diarrhea. Patients with a dysbiotic gut microbiome due to antibiotic therapy, proton pump inhibitors, inflammatory bowel disease, or hospitalization are particularly susceptible to C. difficile infections. Following colonization, C. difficile secretes two toxins, TcdA and TcdB, which contribute to disease symptoms by entering and damaging host cells in the colon. TcdB isotypes from various clinically relevant C. difficile strains exhibit differences in cell tropism and receptor binding capabilities. Specifically, the TcdB2 isotype produced by the hypervirulent, endemic C. difficile strain has evolved to rely on chondroitin sulfate proteoglycan 4 (CSPG4) as its primary cell surface receptor. During injury, CSPG4 functions as a potent signaling molecule when cleaved from the cell surface to promote wound healing. However, since CSPG4 is cleaved from the cell surface, it remains unknown how TcdB2 is internalized by this proteoglycan and whether or not these interactions disrupt CSPG4 function. The overarching goal of this proposal is to understand how CSPG4 is used by TcdB2 to promote the pathologies observed during C. difficile disease. Preliminary evidence suggests TcdB2 residues 1769-1787 facilitate interactions with the chondroitin sulfate (CS) chains of CSPG4 in a divalent cation-dependent fashion to mediate cell entry. Thus, I hypothesize that TcdB2 interacts with the CS chains of CSPG4 to facilitate cell entry and interfere with CSPG4 signaling networks known to be critical for wound healing. In this research training plan, investigations in Aim 1 will determine how interactions between TcdB2 and the CS chains of CSPG4 drive toxin internalization, while Aim 2 will examine how TcdB2 binding impacts known functions regulated by CSPG4. The results of these experiments will provide important insight into the mechanism of TcdB2 uptake by the cell surface proteoglycan CSPG4, and how these interactions contribute to C. difficile disease.


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 = -$23,401 )
2026	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Allergy and Infectious Diseases Research	000	2	12/4/2025	NON-COMPETING CONTINUATION	-$23,401
														Subtotal = -$23,401

Issue Date FY: 2025 ( Subtotal = $37,138 )
2025	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Allergy and Infectious Diseases Research	000	2	1/10/2025	NON-COMPETING CONTINUATION	$36,574
2025	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Allergy and Infectious Diseases Research	001	2	7/28/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $37,138

Issue Date FY: 2024 ( Subtotal = $36,574 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Allergy and Infectious Diseases Research	000	1	1/30/2024	NEW	$35,294
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Allergy and Infectious Diseases Research	001	1	1/30/2024	NEW	$0
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Allergy and Infectious Diseases Research	002	1	5/6/2024	NEW	$1,280
														Subtotal = $36,574

Grand Total All Awards = $50,311

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Toxin B receptor mediated events in Clostridioides difficile disease

Award Number: F31AI179208

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/05/2024

PERIOD OF PERFORMANCE END DATE: 05/09/2025

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