# The role of Gasdermin E (DFNA5) in bacterial keratitis

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $192,768

## Abstract

PROJECT ABSTRACT
Gasdermin (GSDM) A-E comprise a family of pore-forming proteins that are associated with infection,
inflammation and cancer. RNAseq analysis revealed that the only GSDM family members expressed by
neutrophils are Gsdmd and Gsdme/DFNA5, and preliminary data show that neutrophils can activate caspase-
3, which cleaves pro- GSDME to the pore-forming N-GSDME to drive formation of plasma membrane pores
leading to pro-inflammatory pyroptotic cell death. This is in contrast to results from our Nature Communications
2020 paper showing that that GSDMD activated by caspase-1 and neutrophil elastase in neutrophils occurs in
the absence of pyroptotic cell death. Both GSDMD and GSDME mediate neutrophil production of bioactive IL-
1β, which we reported is a pivotal cytokine in the host immune response that is required to
regulate Streptococcus pneumoniae and Pseudomonas aeruginosa bacterial growth and corneal opacification.
We propose to characterize GSDME regulation and function in neutrophils in response to S. pneumoniae
and P. aeruginosa in vitro, and to define the vivo role(s) of GSDME in keratitis caused by these pathogenic
bacteria. Aim 1 will characterize GSDME regulation and function in neutrophils and define its role in
coordinating neutrophil pyroptotic cell death and formation of neutrophil extracellular traps in response to S.
pneumoniae or P. aeruginosa. Aim 2 will characterize GSDME processing in infected corneas, and assess the
role of GSDME in S. pneumoniae or P. aeruginosa using GSDME-/- and GSDME-/-/GSDMD-/- mice in neutrophil
viability, bacterial killing and the severity of corneal disease, and will use an adoptive transfer model to
examine the role of neutrophil GSDME. Results of the proposed studies will provide insight into the role of
these pore forming proteins in neutrophil responses to these ocular pathogens, and will identify potential
targets for immune intervention in bacterial keratitis.

## Key facts

- **NIH application ID:** 10393056
- **Project number:** 5R21EY032662-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** GEORGE R DUBYAK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $192,768
- **Award type:** 5
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393056

## Citation

> US National Institutes of Health, RePORTER application 10393056, The role of Gasdermin E (DFNA5) in bacterial keratitis (5R21EY032662-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10393056. Licensed CC0.

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