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Nat Commun. 2018 Aug 20;9(1):3333. doi: 10.1038/s41467-018-05820-2.

Iron restriction inside macrophages regulates pulmonary host defense against Rhizopus species.

Author information

1
Department of Medicine, University of Crete, Foundation for Research and Technology, 71300, Heraklion, Crete, Greece.
2
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 71300, Heraklion, Crete, Greece.
3
Laboratory of Immunobiology, Center for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece.
4
Division of Infectious Diseases, Los Angeles Biomedical Research Institute, Harbor-University of California Los Angeles (UCLA) Medical Center, 1124 West Carson Street, St. John's Cardiovascular Research Center, Torrance, CA, 90502, USA.
5
Sharjah Institute for Medical Research, College of Pharmacy, University of Sharjah, PO Box 27272, Sharjah, UAE.
6
Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
7
CNRS, BIP (UMR 7281), IMM (FR 3479), Aix-Marseille Université, 31 chemin J. Aiguier, 13402, Marseille, France.
8
Unité des Aspergillus, Institut Pasteur, 75015, Paris, France.
9
Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
10
Division of Infectious Diseases, Los Angeles Biomedical Research Institute, Harbor-University of California Los Angeles (UCLA) Medical Center, 1124 West Carson Street, St. John's Cardiovascular Research Center, Torrance, CA, 90502, USA. ibrahim@labiomed.org.
11
David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. ibrahim@labiomed.org.
12
Department of Medicine, University of Crete, Foundation for Research and Technology, 71300, Heraklion, Crete, Greece. hamilos@imbb.forth.gr.
13
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 71300, Heraklion, Crete, Greece. hamilos@imbb.forth.gr.

Abstract

Mucormycosis is a life-threatening respiratory fungal infection predominantly caused by Rhizopus species. Mucormycosis has incompletely understood pathogenesis, particularly how abnormalities in iron metabolism compromise immune responses. Here we show how, as opposed to other filamentous fungi, Rhizopus spp. establish intracellular persistence inside alveolar macrophages (AMs). Mechanistically, lack of intracellular swelling of Rhizopus conidia results in surface retention of melanin, which induces phagosome maturation arrest through inhibition of LC3-associated phagocytosis. Intracellular inhibition of Rhizopus is an important effector mechanism, as infection of immunocompetent mice with swollen conidia, which evade phagocytosis, results in acute lethality. Concordantly, AM depletion markedly increases susceptibility to mucormycosis. Host and pathogen transcriptomics, iron supplementation studies, and genetic manipulation of iron assimilation of fungal pathways demonstrate that iron restriction inside macrophages regulates immunity against Rhizopus. Our findings shed light on the pathogenetic mechanisms of mucormycosis and reveal the role of macrophage-mediated nutritional immunity against filamentous fungi.

PMID:
30127354
PMCID:
PMC6102248
DOI:
10.1038/s41467-018-05820-2
[Indexed for MEDLINE]
Free PMC Article

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