Author(s):
Gonçalves, Samuel M. ; Duarte-Oliveira, Cláudio ; Campos, Cláudia F. ; Aimanianda, Vishukumar ; ter Horst, Rob ; Leite, Luis ; Mercier, Toine ; Pereira, Paulo N G ; Fernández-García, Miguel ; Antunes, Daniela ; Rodrigues, Cláudia S. ; Barbosa-Matos, Catarina ; Gaifem, Joana ; Mesquita, Inês ; Marques, António ; Osório, Nuno S. ; Torrado, Egídio ; Rodrigues, Fernando ; Costa, Sandra ; Joosten, Leo AB. ; Lagrou, Katrien ; Maertens, Johan ; Lacerda, João ; Campos, António ; Brown, Gordon D. ; Brakhage, Axel A. ; Barbas, Coral ; Silvestre, Ricardo ; van de Veerdonk, Frank L. ; Chamilos, Georgios ; Netea, Mihai G. ; Latgé, Jean-Paul ; Cunha, Cristina ; Carvalho, Agostinho
Date: 2020
Persistent ID: http://hdl.handle.net/10451/55223
Origin: Repositório da Universidade de Lisboa
Project/scholarship:
info:eu-repo/grantAgreement/FCT/POR_NORTE/SFRH%2FBD%2F136814%2F2018/PT;
info:eu-repo/grantAgreement/FCT/POR_NORTE/SFRH%2FBD%2F141127%2F2018/PT;
info:eu-repo/grantAgreement/FCT/POR_NORTE/PD%2FBD%2F137680%2F2018/PT;
info:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FSAU-SER%2F29635%2F2017/PT;
Description
© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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.
This work was supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), the Fundação para a Ciência e Tecnologia (FCT) (SFRH/BD/136814/2018 to S.M.G., SFRH/BD/141127/2018 to C.D.O., PD/BD/137680/2018 to D.A., IF/00474/2014 to N.S.O., IF/01390/2014 to E.T., IF/00959/2014 to S.C., IF/00021/2014 to R.S., PTDC/SAU-SER/29635/2017 and CEECIND/04601/2017 to C.C., and CEECIND/03628/2017 to A.C.), the Institut Mérieux (Mérieux Research Grant 2017 to C.C.), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID Research Grant 2017 to A.C.). M.G.N. was supported by a Spinoza grant of the Netherlands Organization for Scientific Research. A.A.B. was supported by the Deutsche Forschungsgemeinschaft Collaborative Research Center/Transregio TR124 FungiNet (project A1). G.D.B. was funded by the Wellcome Trust (102705), the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1)
