Essential role of hepcidin in host resistance to disseminated candidiasis
Candida albicans is a leading cause of life-threatening invasive infection despite antifungal therapy. Patients with chronic liver disease are at increased risk of candidemia, but the mechanisms underlying this susceptibility are incompletely defined. One consequence of chronic liver disease is an attenuated ability to produce hepcidin and maintain organismal control of iron homeostasis. To address the biology underlying this critical clinical problem, we demonstrate the mechanistic link between hepcidin insufficiency and candida infection using genetic and inducible hepcidin knockout mice. Hepcidin deficiency led to unrestrained fungal growth and increased transition to the invasive hypha morphology with exposed 1,3-β-glucan, which exacerbated kidney injury, independent of the fungal pore-forming toxin candidalysin in immunocompetent mice. Of translational relevance, the therapeutic administration of PR-73, a hepcidin mimetic, improved the outcome of infection. Thus, we identify hepcidin deficiency as a host susceptibility factor against C. albicans and hepcidin mimetics as a potential intervention.
Authors
- Bernhard Hube (ORCID: https://orcid.org/0000-0002-6028-0425)
- Michail S. Lionakis (ORCID: https://orcid.org/0000-0003-4994-9500)
- Borna Mehrad (ORCID: https://orcid.org/0000-0001-5198-065X)
- Dhruv Desai (ORCID: https://orcid.org/0000-0003-2985-6710)
- Sadat Kasem
- Elizabeta Nemeth (ORCID: https://orcid.org/0000-0002-3477-2397)
- Hal Drakesmith (ORCID: https://orcid.org/0000-0002-8503-6103)
- Yogesh Scindia (ORCID: https://orcid.org/0000-0001-6382-6289)
- Divya S. Katikaneni (ORCID: https://orcid.org/0000-0001-7562-3892)
- Nazli Khodayari (ORCID: https://orcid.org/0000-0002-4659-1622)
- Tanmay Arekar
- Sophie Vaulont
- A Cole
- Thrisha Acharya
Institutions
- Centre National de la Recherche Scientifique (FR)
- National Institutes of Health (US)
- Inserm (FR)
- University of California, Los Angeles (US)
- Université Paris Cité (FR)
- University of Florida (US)
- University of Oxford (GB)
- MRC Weatherall Institute of Molecular Medicine (GB)
- National Institute of Allergy and Infectious Diseases (US)
- Institut Cochin (FR)
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115649
- Citations
- 4
- Primary Topic
- Clostridium difficile and Clostridium perfringens research
- Type
- article
- Field-Weighted Citation Impact
- 5.58
Funders
- W. M. Keck Foundation
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Vifor Pharma
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases