Iron restriction inside macrophages regulates pulmonary host defense against Rhizopus species

• DOI: 10.1038/s41467-018-05820-2
• Publication Date: 2018-08-14T13:11:09Z
• Authors: Angeliki M. Andri...; Irene Kyrmizi; Kalliopi Thanopoulou; Clara Baldin; Elias Drakos; Sameh S. M. Soliman; Amol C. Shetty; Carrie McCracken; Tonia Akoumianaki; Kostas Stylianou; Petros Ioannou; Charalampos Ponti...; Helen A. Papadaki; Maria Tzardi; Valerie Belle; Emilien Etienne; Anne Beauvais; George Samonis; Dimitrios P. Kont...; Evangelos Andreakos; Vincent M. Bruno; Ashraf S. Ibrahim; Georgios Chamilos
• Keywords: Spores; Fungal infection; 0301 basic medicine; [SDV]Life Sciences [q-bio]; Inbred C57BL; Mice; Models; Cell Wall; Phagosomes; 2.1 Biological and endogenous factors; 2.2 Factors relating to the physical environment; Aetiology; Lung; [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology; Q; Biological Sciences; Spores, Fungal; [SDV] Life Sciences [q-bio]; Infectious Diseases; Fungal; Medical Microbiology; Host-Pathogen Interactions; Fungal pathogenesis; Infection; Rhizopus; Science; Iron; Clinical Sciences; 610; Alveolar; Microbiology; Models, Biological; Article; 03 medical and health sciences; Macrophages, Alveolar; Animals; Mucormycosis; Melanins; Microbial Viability; Biomedical and Clinical Sciences; Inflammatory and immune system; Macrophages; Biological; [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology; [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology; Fungal host response; Mice, Inbred C57BL; Emerging Infectious Diseases; Gene Expression Regulation; [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology

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