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Nat Commun . 2020 May 8;

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

Liron Malki, Ofer Sarig, Nicole Cesarato, Janan Mohamad, Talia Canter, Sari Assaf, Mor Pavlovsky, Dan Vodo, Yossi Anis, Ofer Bihari, Kiril Malovitski, Andrea Gat, Holger Thiele, Bethany E Perez White, Liat Samuelov, Arti Nanda, Amy S Paller, Regina C Betz, Eli Sprecher, Xueyi Shen, David M Howard, Mark J Adams, W David Hill, Toni-Kim Clarke, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Ian J Deary, Heather C Whalley, Andrew M McIntosh, Samuel M Gonçalves, Cláudio Duarte-Oliveira, Cláudia F Campos, Vishukumar Aimanianda, Rob Ter Horst, Luis Leite, Toine Mercier, Paulo Pereira, Miguel Fernández-García, Daniela Antunes, Cláudia S Rodrigues, Catarina Barbosa-Matos, Joana Gaifem, Inês Mesquita, António Marques, Nuno S Osório, Egídio Torrado, Fernando Rodrigues, Sandra Costa, Leo Ab Joosten, Katrien Lagrou, Johan Maertens, João F Lacerda, António Campos Jr, Gordon D Brown, Axel A Brakhage, Coral Barbas, Ricardo Silvestre, Frank L van de Veerdonk, Georgios Chamilos, Mihai G Netea, Jean-Paul Latgé, Cristina Cunha, Agostinho Carvalho

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.

PMID: 32385235