# Elucidating pathways that regulate fungal keratitis pathogenesis

> **NIH NIH P20** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2022 · $275,136

## Abstract

Project Summary/Abstract 
Fungal keratitis is an important source of ocular morbidity and unilateral blindness worldwide. Current 
antifungal regimes fails in up to 60% of patients, resulting in the need for at least one and sometimes 
repeated corneal transplants. Novel antifungals are therefore required, but their development requires 
a better understanding of fungal proteins/enzymes that could serve as drug targets. As the corneal 
stroma is effectively an extracellular matrix comprised of collagen and other proteins, we hypothesize 
that pathways that support fungal protein catabolism are essential for fungal growth in the eye and, by 
extension, virulence factors that might be targeted in treatment. 
In order for fungi to utilize proteins as a nutritional source, they must first secrete copious amounts of 
proteases into the environment/host tissue. This secretory burden leads to an accumulation of 
unfolded proteins within the endoplasmic reticulum (ER) that, if not resolved, leads to a “clogging” of the 
secretion pathway that will severely inhibit fungal growth. The unfolded protein response (UPR) plays a 
critical role in this regard by first sensing unfolded proteins and subsequently regulating genes that that 
promote the protein folding capacity within the ER lumen (e.g., chaperones). In Aim 1, we will test the 
hypothesis that fungal UPR promotes the corneal pathogenesis of a common agent of keratitis, 
Fusarium solani. We will first generate UPR-deficient mutants of F. solani and then test whether the 
mutants are defective for growth on protein substrates as we predict. We will then assess the virulence 
of the mutants in a mouse model of fungal keratitis. The observation that the UPR-deficient strains are 
hypovirulent would suggest that inhibitors of the UPR could be used as novel antifungals. 
The transcriptional profile of a fungus varies largely as a function of the nutrient source. The transition 
from glucose-rich to glucose-limiting media, for example, leads to a down-regulation of glycolytic genes, 
upregulation of secreted hydrolases, and an upregulation of metabolic enzymes involved in amino acid 
metabolism. Therefore, in Aim 2, we will test the hypothesis that the F. solani utilizes proteins in the 
cornea by comparing the transcriptome of the fungus in vivo (from infected eyes) against the 
transcriptome of the fungus grown under defined nutrient conditions (collagen v. glucose) in vitro. We 
predict that the most highly expressed genes in vivo will mirror the most highly expressed genes on 
collagen. However, we do not expect a one-to-one correspondence between the two datasets due to 
environmental conditions that are unique to the eye, such as stresses imparted by the inflammatory 
response. In this way, we stand to gain novel insight into the fungal adaptive response during keratitis 
infection, which will lead to the identification of novel virulence genes and putative drug targets.

## Key facts

- **NIH application ID:** 10341206
- **Project number:** 5P20GM134973-03
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Kevin K. Fuller
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $275,136
- **Award type:** 5
- **Project period:** 2020-03-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10341206

## Citation

> US National Institutes of Health, RePORTER application 10341206, Elucidating pathways that regulate fungal keratitis pathogenesis (5P20GM134973-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10341206. Licensed CC0.

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