Work

Metabolic imprinting drives epithelial memory during mucosal fungal infection

Year: 2025

Type: preprint

Abstract: Epithelial cells at barrier sites are emerging as active participants in innate immune memory, yet the underlying metabolic and epigenetic mechanisms remain unclear. Here, we uncover a previously unrecognized form of trained immunity in oral epithelial cells that enhances protection against fungal infection. Using a mouse model, we show that mucosal exposure to Candida albicans confers sustained protective memory that is independent of adaptive immunity and myeloid cells. Mechanistically, mucosal memory is driven by proline catabolism via proline dehydrogenase (Prodh) in epithelial cells, which sustains mitochondrial function, epigenetic remodeling, and promotes cytokine production upon secondary challenge. Unlike classical trained immunity in immune cells, epithelial memory is independent of glycolysis but partially sustained by fatty acid oxidation via carnitine palmitoyltransferase-I (CPT1). These findings uncover a distinct metabolic-epigenetic axis that underlines long-term epithelial memory in the oral mucosa and reveal novel non-hematopoietic mechanisms of mucosal defense against fungal pathogens.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/2025.07.11.664387

Authors: Jinendiran Sekar, Norma V. Solis, Jian Miao, Nicolas Millet, Bryce Tom, Derek Quintanilla, Aize Pellon, David L. Moyes, Joseph A. Gogos, Harry B. Rossiter, Scott G. Filler, Mihai G. Netea, Jennifer K. Yee, Marc Swidergall

Institutions: University of California, Los Angeles, The Lundquist Institute, Harbor–UCLA Medical Center, King's College London, CIC bioGUNE, Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, University of Bonn, Radboud University Nijmegen, Radboud University Medical Center

Language: English

Topic: Immune responses and vaccinations

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Dental and Craniofacial Research

Awards: COPD cachexia: deciphering the impact of antioxidants, iron and mitochondrial function using 'omics approaches, ACTIV Integration of Host-targeting Therapies for COVID-19 Administrative Coordinating Center, Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis, Center for Male Reproductive Epigenomics, A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients, Determinants of 5 Year Progression of Muscle Dysfunction and Inactivity in COPDGene Participants., Oral commensal fungi and structural immunity, Systems Epigenomics of Persistent Bloodstream Infection, Novel cardiopulmonary exercise testing variables to differentiate neuromuscular deconditioning from disease

OpenAlex ID: W4412960604

Cites: 81

Cited by: 2

Related to: 10