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

Award Number: R01AI168411
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/14/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $771,486 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	2	11/4/2024	NON-COMPETING CONTINUATION	$771,486
														Subtotal = $771,486

Issue Date FY: 2024 ( Subtotal = $808,926 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	11/14/2023	NEW	$729,559
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	1	9/4/2024	NEW	$79,367
														Subtotal = $808,926

Grand Total All Awards = $1,580,412

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

Award Number: R01AI168411

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 11/14/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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