# Pathogenesis of Bacterial Keratitis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $705,516

## Abstract

Abstract
 The pathogenic bacteria Pseudomonas aeruginosa is a major cause of blinding corneal
infections in the USA and worldwide. This includes a recent outbreak of drug resistant P.
aeruginosa keratitis in contaminated eyedrops that caused keratitis in 68 patients from 16 US
states and resulted in 3 deaths and 8 enucleations. Our earlier studies supported by this grant
demonstrated that P. aeruginosa virulence in infected corneas is due to expression of the Type
III secretion system, which comprises a needle structure that injects exoenzymes directly into
the host cell cytosol. Our recent data show that using either NLRP3-/- mice or the NLRP3 small
molecule inhibitor MCC950, P. aeruginosa ExoS ADP ribosyl transferase (ADPRT) selectively
licenses NLRP3 inflammasome usage in neutrophils (where macrophages use the NLRC4
inflammasome) for IL-1β processing and secretion, and importantly that NLRP3 is required for
effective bacterial killing in infected corneas that can be blocked with the small molecule
inhibitor MCC950. Proposed studies in Aim 1 will examine the early events in NLRP3 activation
in neutrophils, including a role for NEK7 and HDAC6, which will also be examined during
infection. Aim 2 will use an HEK293 based expression system to produce mg levels of NLRP3
that can used to identifying NLRP3 domains and specific arginine residues that are targeted by
ExoS ADPRT. Aim 3 will examine cell death pathways in corneal epithelial cells and neutrophils
infected with P. aeruginosa expressing the Type II secretion protein ToxA and determine if there
is a role for NLRP1 pyroptotic cell death and in corneal infections. Results of these proposed
studies will identify novel targets for immune intervention in this blinding infection.

## Key facts

- **NIH application ID:** 10883532
- **Project number:** 2R01EY014362-20
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** GEORGE R DUBYAK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $705,516
- **Award type:** 2
- **Project period:** 2003-04-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883532

## Citation

> US National Institutes of Health, RePORTER application 10883532, Pathogenesis of Bacterial Keratitis (2R01EY014362-20). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10883532. Licensed CC0.

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