# Innate immune responses to tissue infection by intestinal fungi inhibit wound repair

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $808,926

## Abstract

ABSTRACT
Alterations of the mycobiome composition that have been associated with Crohn’s disease (CD) are challenging
to link to defining elements of pathophysiology of this disease such as poor injury repair. Our published work
shows that using culture dependent and independent methods, Debaryomyces hansenii, a yeast best known for
its role as an additive in the food industry, is the dominant microbe found to non-healed intestinal wounds of
subjects with CD in two different medical centers. D. hansenii was not found in adjacent healthy tissue. D.
hansenii strains cultured from inflamed CD mucosal tissue impaired colonic healing when introduced into injured
conventionally raised or gnotobiotic mice. D. hansenii was re-isolated from injured areas of these mice, fulfilling
Koch’s postulates using animal models. Mechanistically, D. hansenii impaired mucosal healing via macrophage
production of type 1 Interferon (IFN) (not traditional proinflammatory cytokines such as TNF) that in turn led to
overproduction of the chemokine CCL5 a driver of poor repair. We have new preliminary data that shows D.
hansenii spores and vegetative cells are both important to the overall pathology of poor wound repair in the
intestine. We hypothesize that in damaged intestines, D. hansenii spores are taken up by F4/80+ innate immune
cells in the wound bed without eliciting a TNF response thereby allowing for persistence within the macrophage.
We also hypothesize that these D. hansenii spores germinate into vegetative cells within these macrophages.
This process stimulates type I IFN production through TLR3 engagement and this immune response prevents
wound healing. Our goals are to determine how D. hansenii spores evade macrophage killing (Aim 1) and how
germinating/vegetative cells can stimulate type I IFN (Aim 2). In Aim 3, we will also develop tools for the detection
of D. hansenii spores and vegetative cells in murine models of injury and we will use these tools to determine in
preclinical models to determine if antifungal therapy can effectively eradicate cells in different morphologies with
the goal of restoring wound healing. Our studies will provide tools new knowledge to understand why D. hansenii
behaves as a pathogen in CD, and we will use this information to develop concepts for new diagnostics and
therapies for CD patients.

## Key facts

- **NIH application ID:** 10801062
- **Project number:** 1R01AI168411-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** DEBORAH A HOGAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $808,926
- **Award type:** 1
- **Project period:** 2023-11-14 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801062

## Citation

> US National Institutes of Health, RePORTER application 10801062, Innate immune responses to tissue infection by intestinal fungi inhibit wound repair (1R01AI168411-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10801062. Licensed CC0.

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