# Novel treatment strategies to regulate inflammation during P.aeruginosa keratitis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $439,875

## Abstract

Abstract
Pseudomonas aeruginosa–induced corneal keratitis is a sight-threatening disease. The rising antibiotic
resistance among the Pseudomonas isolates makes treatment of this disease challenging, justifying the need
for alternative therapeutic modalities. We propose to explore the concept that exposure of ocular surfaces to
commensal strains or perturbations of commensal ecosystems alters the bactericidal capability of neutrophils
against P. aeruginosa, thereby determining the threshold for susceptibility to infection.
Specific Aim 1. Define the impact of ocular exposure to commensal strains on susceptibility to P.
aeruginosa-induced keratitis.
We demonstrated that there was a measurable and significant impact of ocular exposure to commensal
organisms that strengthens the immune responses to P. aeruginosa-induced keratitis. In this aim, we will
colonize conjunctival mucosal surfaces with different commensal organisms and evaluate the consequences of
colonization on P. aeruginosa-induced keratitis.
Specific Aim 2. Define the impact of gut microbiota on neutrophil bactericidal activities at baseline and
during P. aeruginosa-induced keratitis.
Reduction of gut microbiota has a pronounced impact on susceptibility to keratitis, signifying the existence of a
mechanism operating along a “gut-eye” axis. In this aim we will identify gut commensal communities that
regulate neutrophil bactericidal properties against P. aeruginosa. We will utilize selective antibiotic-based
reduction of commensal organisms and colonization of germ free mice with different commensal communities
to evaluate how gut commensals affect neutrophil bactericidal properties and, thereby, cause susceptibility to
keratitis. We will leverage our experience in quantitative transcriptomic and proteomic analysis to gain insights
into microbiota-driven granulocyte maturation and examine the mechanisms thereof.
Specific Aim 3. Evaluate the impact of MIF deficiency on commensal presence and development of
keratitis.
MIF deficiency confers resistance to P. aeruginosa-induced keratitis and, excitingly, commensal communities
in MIF-deficient mice are more diverse than those of MIF-sufficient mice. We will explore how these alterations
in commensal presence affect resistance to infection by decreasing commensal abundance either locally or in
the gut through selective antibiotic treatments.

## Key facts

- **NIH application ID:** 9997938
- **Project number:** 5R01EY022054-09
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Mihaela Gueorguieva Gadjeva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $439,875
- **Award type:** 5
- **Project period:** 2012-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997938

## Citation

> US National Institutes of Health, RePORTER application 9997938, Novel treatment strategies to regulate inflammation during P.aeruginosa keratitis (5R01EY022054-09). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9997938. Licensed CC0.

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