Iron restriction inside macrophages regulates pulmonary host defense against Rhizopus species

Angeliki M. Andrianaki, Irene Kyrmizi, Kalliopi Thanopoulou, Clara Baldin, Elias Drakos, Sameh S. M. Soliman, Amol C. Shetty, Carrie McCracken, Tonia Akoumianaki, Kostas Stylianou, Petros Ioannou, Charalampos Pontikoglou, Helen A. Papadaki, Maria Tzardi, Valerie Belle, Emilien Etienne, Anne Beauvais, George Samonis, Dimitrios P. Kontoyiannis, Evangelos Andreakos, Vincent M. Bruno, Ashraf S. Ibrahim () and Georgios Chamilos ()
Additional contact information
Angeliki M. Andrianaki: University of Crete, Foundation for Research and Technology
Irene Kyrmizi: University of Crete, Foundation for Research and Technology
Kalliopi Thanopoulou: Biomedical Research Foundation of the Academy of Athens
Clara Baldin: Harbor-University of California Los Angeles (UCLA) Medical Center
Elias Drakos: University of Crete, Foundation for Research and Technology
Sameh S. M. Soliman: University of Sharjah
Amol C. Shetty: University of Maryland School of Medicine
Carrie McCracken: University of Maryland School of Medicine
Tonia Akoumianaki: University of Crete, Foundation for Research and Technology
Kostas Stylianou: University of Crete, Foundation for Research and Technology
Petros Ioannou: University of Crete, Foundation for Research and Technology
Charalampos Pontikoglou: University of Crete, Foundation for Research and Technology
Helen A. Papadaki: University of Crete, Foundation for Research and Technology
Maria Tzardi: University of Crete, Foundation for Research and Technology
Valerie Belle: Aix-Marseille Université
Emilien Etienne: Aix-Marseille Université
Anne Beauvais: Institut Pasteur
George Samonis: University of Crete, Foundation for Research and Technology
Dimitrios P. Kontoyiannis: The University of Texas MD Anderson Cancer Center
Evangelos Andreakos: Biomedical Research Foundation of the Academy of Athens
Vincent M. Bruno: University of Maryland School of Medicine
Ashraf S. Ibrahim: Harbor-University of California Los Angeles (UCLA) Medical Center
Georgios Chamilos: University of Crete, Foundation for Research and Technology

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05820-2

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