TY - JOUR
T1 - Iron restriction inside macrophages regulates pulmonary host defense against Rhizopus species
AU - Andrianaki, Angeliki M.
AU - Kyrmizi, Irene
AU - Thanopoulou, Kalliopi
AU - Baldin, Clara
AU - Drakos, Elias
AU - Soliman, Sameh S.M.
AU - Shetty, Amol C.
AU - McCracken, Carrie
AU - Akoumianaki, Tonia
AU - Stylianou, Kostas
AU - Ioannou, Petros
AU - Pontikoglou, Charalampos
AU - Papadaki, Helen A.
AU - Tzardi, Maria
AU - Belle, Valerie
AU - Ettiene, Emilien
AU - Beauvais, Anne
AU - Samonis, George
AU - Kontoyiannis, Dimitrios P.
AU - Andreakos, Evangelos
AU - Bruno, Vincent M.
AU - Ibrahim, Ashraf S.
AU - Chamilos, Georgios
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-018-05820-2
DO - 10.1038/s41467-018-05820-2
M3 - Article
C2 - 30127354
AN - SCOPUS:85051929470
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3333
ER -