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Bacterial Cholesterol-Dependent Cytolysins in Inflammasome Activation

Award Number: R01AI182143
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: 01/24/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Bacterial Cholesterol-Dependent Cytolysins in Inflammasome Activation - PROJECT SUMMARY Bacterial cholesterol-dependent cytolysins (CDCs) constitute the largest group of pore-forming toxins and serve as critical virulence factors for a wide variety of pathogenic bacteria. A number of CDCs are known to activate the NLRP3 inflammasome, a multiprotein innate immune signaling complex responsible for induction of proinflammatory cytokines (e.g., IL-1β and IL-18) and the proinflammatory cell death pyroptosis. Inhibition of NLRP3 inflammasome has been shown to significantly affect bacterial dissemination and pathogenesis. However, the detailed molecular and cellular mechanism underlying CDC-mediated inflammasome activation has not been fully characterized. In this proposal, we propose that CDCs can be grouped into two types based on whether they can directly remodel host organelle to stimulate the NLRP3 inflammasome signaling. This helps the host organisms clear invading bacteria, although excessive inflammation may also result in pathogenesis. Using a combination of SunTag live cell imaging, mass spectrometry analysis and infection models, we aim to define the motifs and host factors responsible for CDCs to reorganize host organelle and activate the NLRP3 inflammasome. We will also determine and characterize the abilities of Type II CDCs to escape the inflammasome activation via inhibition of host organelle remodeling. Our proposed studies will help define this host organelle remodeling activity of bacterial CDCs as potential broad-spectrum therapeutic targets to mitigate a wide range of infectious diseases.


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 = $522,056 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	2	12/31/2025	NON-COMPETING CONTINUATION	$522,056
														Subtotal = $522,056

Issue Date FY: 2025 ( Subtotal = $506,394 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	1/24/2025	NEW	$506,394
														Subtotal = $506,394

Grand Total All Awards = $1,028,450

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Bacterial Cholesterol-Dependent Cytolysins in Inflammasome Activation

Award Number: R01AI182143

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: 01/24/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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