# Pathogenesis of Fungal Keratitis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $419,494

## Abstract

Abstract
 Pathogenic Fusarium and Aspergillus molds are an important cause of vision loss in the USA and
worldwide. Preliminary data from an unbiased gene array analyses (Nanostring and RNA sequencing) showed
an anticipated increase in expression of multiple genes in neutrophils isolated from Fusarium and Aspergillus
infected mouse corneas compared with bone marrow neutrophils from the same mice. However, we found an
unexpected significant increase in expression of the pro-inflammatory cytokine IL-1 alpha, and of
Spp1/osteopontin (OPN), which has known pro-inflammatory activity, and which exists as a secreted (sOPN)
and intracellular (iOPN). Elevated IL-1 alpha and OPN was confirmed by Q-PCR, ELISA and intracellular flow
cytometry. Aim 1 will characterize the membrane, secreted and intracellular activities the pro- and cleaved
forms of IL-1 alpha in murine and human neutrophils, and in Fusarium and Aspergillus keratitis. Aim 2 will
identify regulators of OPN expression, and use OPN-/- and iOPN knock-in mice to examine the role of the
intracellular versus secreted forms of this protein in human neutrophils and in fungal keratitis. Aim 3 will
characterize the role of neutrophil extracellular traps (NETs), which can limit hyphal growth, but also have the
potential to contribute to tissue damage. Proposed experiments will identify the molecular pathways leading to
NET formation in infected corneas, and using mice that lack the enzyme required for histone citrullinatation and
decondensation (PAD4), we will examine the role of NETs in Fusarium and Aspergillus keratitis. Collectively,
the results of these proposed studies will increase our understanding of the pathogenesis of this blinding
disease, and will potentially identify novel targets for immune intervention to prevent neutrophil mediated tissue
damage and loss of corneal clarity.

## Key facts

- **NIH application ID:** 9846210
- **Project number:** 5R01EY018612-12
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Eric Pearlman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,494
- **Award type:** 5
- **Project period:** 2008-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846210

## Citation

> US National Institutes of Health, RePORTER application 9846210, Pathogenesis of Fungal Keratitis (5R01EY018612-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9846210. Licensed CC0.

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