Phagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity
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Published:2020-05-08
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Gonçalves Samuel M., Duarte-Oliveira Cláudio, Campos Cláudia F., Aimanianda Vishukumar, ter Horst RobORCID, Leite Luis, Mercier ToineORCID, Pereira PauloORCID, Fernández-García Miguel, Antunes DanielaORCID, Rodrigues Cláudia S., Barbosa-Matos CatarinaORCID, Gaifem Joana, Mesquita Inês, Marques António, Osório Nuno S.ORCID, Torrado EgídioORCID, Rodrigues Fernando, Costa Sandra, Joosten Leo AB.ORCID, Lagrou KatrienORCID, Maertens Johan, Lacerda João F., Campos António, Brown Gordon D., Brakhage Axel A., Barbas CoralORCID, Silvestre RicardoORCID, van de Veerdonk Frank L., Chamilos Georgios, Netea Mihai G.ORCID, Latgé Jean-PaulORCID, Cunha CristinaORCID, Carvalho AgostinhoORCID
Abstract
AbstractIn 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.
Funder
EC | European Regional Development Fund Ministry of Education and Science | Fundação para a Ciência e a Tecnologia European Society of Clinical Microbiology and Infectious Diseases
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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