Journal Article

Phagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity

Pereira, Paulo, Fernández-García, Miguel, Brown, Gordon D., Barbas, Coral, Mesquita, Inês, Torrado, Egídio, ter Horst, Rob, Antunes, Daniela, Maertens, Johan, Joosten, Leo AB, Aimanianda, Vishukumar, Latgé, Jean-Paul, Silvestre, Ricardo, Campos, Cláudia F., Mercier, Toine, Carvalho, Agostinho, Barbosa-Matos, Catarina, Leite, Luis, Duarte-Oliveira, Cláudio, Brakhage, Axel A., Chamilos, Georgios, Cunha, Cristina, Rodrigues, Cláudia S., Campos, António, Rodrigues, Fernando, Netea, Mihai G., Gonçalves, Samuel M., Marques, António, Lagrou, Katrien, Costa, Sandra, van de Veerdonk, Frank L., Lacerda, João F., Gaifem, Joana, Osório, Nuno S.

2020

Overview

In response to infection, macrophages adapt their metabolism rapidly to enhance glycolysis and fuel specialized antimicrobial effector functions. Here we show that fungal melanin is an essential molecule required for the metabolic rewiring of macrophages during infection with the fungal pathogen Aspergillus fumigatus . Using pharmacological and genetic tools, we reveal a molecular link between calcium sequestration by melanin inside the phagosome and induction of glycolysis required for efficient innate immune responses. By remodeling the intracellular calcium machinery and impairing signaling via calmodulin, melanin drives an immunometabolic signaling axis towards glycolysis with activation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) and phagosomal recruitment of mammalian target of rapamycin (mTOR). These data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during fungal infection and highlight the metabolic repurposing of immune cells as a potential therapeutic strategy. Macrophages undergo a Warburg-like switch from oxidative phosphorylation to glycolysis in response to inflammatory stimulus. Here the authors show that fungal melanin can trigger this switch in human macrophages by sequestering calcium in the phagosome and enabling protection against Aspergillus fumigatus infection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/21 / 13/31 / 14 / 14/1 / 14/19 / 38 / 38/91 / 45 / 631/250/248 / 631/250/2499 / 631/45/127/1213 / 631/45/320 / 631/80/304 / 64 / 64/60 / 96 / Animals / Antifungal agents / Aspergillus fumigatus / Aspergillus fumigatus - immunology / Calcium / Calcium (intracellular) / Calcium sequestration / Calcium Signaling / Calcium signalling / Calcium-binding protein / Calmodulin / Cell Behavior / Cellular Biology / Fungi / Fungicides / Glucose - metabolism / Glycolysis / Humanities and Social Sciences / Humans / Hypoxia / Hypoxia-inducible factor 1 / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Hypoxia-inducible factors / Immune response / Immune system / Immunity / Infections / Inflammation / Innate immunity / Intracellular signalling / Lactates - metabolism / Life Sciences / Macrophages / Macrophages - immunology / Macrophages - microbiology / Melanin / Melanins - metabolism / Metabolism / Mice, Inbred C57BL / multidisciplinary / Oxidative phosphorylation / Phagosomes - metabolism / Phosphorylation / Rapamycin / Rewiring / Science / Science (multidisciplinary) / Sequestering / Signaling / TOR protein / TOR Serine-Threonine Kinases - metabolism / Transcriptome - genetics