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

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 A.B. JoostenKatrien 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
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Abstract

In response to infection, macrophages rapidly adapt their metabolic programs whereby enhanced glycolysis fuels specialized antimicrobial effector functions. We establish fungal melanin as an essential molecule required for the metabolic rewiring of macrophages during infection with the fungal pathogen Aspergillus fumigatus. Using different 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 involving the activation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) and that requires the 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.
Original languageEnglish
Article number2282
JournalNature Communications
Volume11
Early online date8 May 2020
DOIs
Publication statusPublished - 2020

Keywords

  • Aspergillus
  • melanin
  • immunometabolism
  • glycolysis
  • calcium
  • macrophage
  • antifungal immunity
  • invasive pulmonary aspergillosis
  • ACTIVATION
  • ASPERGILLUS-FUMIGATUS
  • PHAGOCYTOSIS
  • DENDRITIC CELL
  • CONIDIA
  • MTOR
  • SUCCINATE-DEHYDROGENASE
  • INHIBITION
  • BIOSYNTHESIS
  • CELLULAR-METABOLISM

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