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


ABSTRACT: 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-1?) 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.

SUBMITTER: Goncalves SM 

PROVIDER: S-EPMC7210971 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Gonçalves Samuel M SM   Duarte-Oliveira Cláudio C   Campos Cláudia F CF   Aimanianda Vishukumar V   Ter Horst Rob R   Leite Luis L   Mercier Toine T   Pereira Paulo P   Fernández-García Miguel M   Antunes Daniela D   Rodrigues Cláudia S CS   Barbosa-Matos Catarina C   Gaifem Joana J   Mesquita Inês I   Marques António A   Osório Nuno S NS   Torrado Egídio E   Rodrigues Fernando F   Costa Sandra S   Joosten Leo Ab LA   Lagrou Katrien K   Maertens Johan J   Lacerda João F JF   Campos António A   Brown Gordon D GD   Brakhage Axel A AA   Barbas Coral C   Silvestre Ricardo R   van de Veerdonk Frank L FL   Chamilos Georgios G   Netea Mihai G MG   Latgé Jean-Paul JP   Cunha Cristina C   Carvalho Agostinho A  

Nature communications 20200508 1


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  ...[more]

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