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

Nature communications (2018-08-22)
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, Georgios Chamilos

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.

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Fluorescein isothiocyanate–dextran, average mol wt 70,000, (FITC:Glucose = 1:250)
Iron(III) chloride, reagent grade, 97%