Essential role of hepcidin in host resistance to disseminated candidiasis
Tanmay Arekar,
Divya Katikaneni,
Sadat Kasem,
Dhruv Desai,
Thrisha Acharya,
Augustina Cole,
Nazli Khodayari,
Sophie Vaulont,
Bernhard Hube,
Elizabeta Nemeth,
Alexander Drakesmith,
Michail S. Lionakis,
Borna Mehrad,
Yogesh Scindia
Affiliations
Tanmay Arekar
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
Divya Katikaneni
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
Sadat Kasem
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
Dhruv Desai
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
Thrisha Acharya
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
Augustina Cole
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
Nazli Khodayari
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
Sophie Vaulont
Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France
Bernhard Hube
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Jena, Germany
Elizabeta Nemeth
Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Alexander Drakesmith
MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Michail S. Lionakis
Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA
Borna Mehrad
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA
Yogesh Scindia
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA; Center for Integrated Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA; Corresponding author
Summary: 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.
