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Inflammasome-mediated corneal epithelial cell defenses inhibited by pathogenic bacteria

Award Number: R01EY034239
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Inflammasome-mediated corneal epithelial cell defenses inhibited by pathogenic bacteria - Project Summary/Abstract The healthy corneal epithelium is an effective barrier to pathogenic and environmental bacteria. Because of this, corneal infection or keratitis models often rely on bypassing the epithelium altogether by introducing microbes directly into the corneal stroma, where they initiate immune cell responses that can damage tissue and cause vision-threatening scarring. A limitation of this experimental approach is that epithelial defense mechanisms are unable to be identified or investigated. The bacterial pathogen Pseudomonas aeruginosa is the most common infection associated with soft contact lens wear, suggesting it is uniquely capable of causing infection in the stroma even when the epithelium remains intact. One way in which P. aeruginosa colonizes the epithelium is by invading and replicating inside epithelial cells, which has been investigated in cultured cells, and observed in mouse corneal infection models. Preliminary data show that the toxin ExoS produced by P. aeruginosa suppresses caspase-4 mediated pyroptosis of invaded corneal epithelial cells, buying time for bacteria to replicate in a protected niche. Additional data indicate that a different inflammasome pathway is also active in corneal epithelial cells, and leads to production of the cytokine IL-1β, which ExoS also suppresses. Therefore, a novel role for ExoS in corneal infection could be to prolong a niche for bacteria to replicate within corneal epithelial cells, while limiting secretion of cytokines that recruit immune cells. Using imaging methods to selectively monitor invaded cells, and CRISPR-Cas9 to manipulate corneal epithelial cells genetically, we will answer three outstanding questions regarding both corneal epithelial defense, and bacterial subversion of it: 1. How does ExoS block caspase-4-mediated pyroptosis? 2. How do corneal epithelial cells detect and respond to P. aeruginosa? 3. What is the significance of epithelial cell inflammasome activation and pyroptosis in protecting the eye from developing keratitis in the stroma? Successful completion of these aims will identify a new mechanism of host defense at the ocular surface, further our understanding of inflammasomes in epithelial cells, and elucidate how a uniquely devastating corneal pathogen is able to overcome host defenses.


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 = $377,305 )
2025	2025	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Vision Research	000	4	4/11/2025	NON-COMPETING CONTINUATION	$377,305
														Subtotal = $377,305

Issue Date FY: 2024 ( Subtotal = $377,305 )
2024	2024	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Vision Research	000	3	5/22/2024	NON-COMPETING CONTINUATION	$377,305
														Subtotal = $377,305

Issue Date FY: 2023 ( Subtotal = $377,305 )
2023	2023	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Vision Research	000	2	5/8/2023	NON-COMPETING CONTINUATION	$377,305
														Subtotal = $377,305

Issue Date FY: 2022 ( Subtotal = $377,305 )
2022	2022	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Vision Research	000	1	8/22/2022	NEW	$377,305
														Subtotal = $377,305

Grand Total All Awards = $1,509,220

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Inflammasome-mediated corneal epithelial cell defenses inhibited by pathogenic bacteria

Award Number: R01EY034239

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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