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

Animals Aspergillus fumigatus / immunology Calcium Signaling Glucose / metabolism Glycolysis Humans Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Immunity Lactates / metabolism Macrophages / immunology Melanins / metabolism Mice, Inbred C57BL Phagosomes / metabolism TOR Serine-Threonine Kinases / metabolism Transcriptome / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
08 05 2020
Historique:
received: 19 07 2019
accepted: 14 04 2020
entrez: 10 5 2020
pubmed: 10 5 2020
medline: 6 8 2020
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-020-16120-z PMID: 32385235 PMC: PMC7210971
pubmed: 32385235
doi: 10.1038/s41467-020-16120-z
pii: 10.1038/s41467-020-16120-z
pmc: PMC7210971
doi:

Substances chimiques

Hypoxia-Inducible Factor 1, alpha Subunit 0
Lactates 0
Melanins 0
TOR Serine-Threonine Kinases EC 2.7.11.1
Glucose IY9XDZ35W2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2282

Subventions

Organisme : Medical Research Council
ID : MR/N006364/2
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 102705
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N006364/1
Pays : United Kingdom

Commentaires et corrections

Type : CommentIn

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Auteurs

Samuel M Gonçalves (SM)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.

Cláudio Duarte-Oliveira (C)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.

Cláudia F Campos (CF)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.

Vishukumar Aimanianda (V)

Unité des Aspergillus, Institut Pasteur, 75015, Paris, France.

Rob Ter Horst (R)

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Centre, 6500HB, Nijmegen, Netherlands.
ORCID: 0000-0003-0576-5873

Luis Leite (L)

STMO, Instituto Português de Oncologia, 4200-072, Porto, Portugal.

Toine Mercier (T)

Department of Hematology, UZ Leuven, 3000, Leuven, Belgium.
Department of Microbiology and Immunology, KU Leuven, 3000, Leuven, Belgium.
ORCID: 0000-0002-1517-6426

Paulo Pereira (P)

Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, 1649-028, Lisboa, Portugal.
ORCID: 0000-0002-0930-0902

Miguel Fernández-García (M)

Center for Metabolomics and Bioanalysis, Faculty of Pharmacy, San Pablo CEU University, 28668, Madrid, Spain.

Daniela Antunes (D)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.
ORCID: 0000-0002-2696-5068

Cláudia S Rodrigues (CS)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.

Catarina Barbosa-Matos (C)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.
ORCID: 0000-0003-1031-4241

Joana Gaifem (J)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.

Inês Mesquita (I)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.

António Marques (A)

Serviço de Imuno-Hemoterapia, Hospital de Braga, 4710-243, Braga, Portugal.

Nuno S Osório (NS)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.
ORCID: 0000-0003-0949-5399

Egídio Torrado (E)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.
ORCID: 0000-0002-7462-8234

Fernando Rodrigues (F)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.

Sandra Costa (S)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.

Leo Ab Joosten (LA)

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Centre, 6500HB, Nijmegen, Netherlands.
ORCID: 0000-0001-6166-9830

Katrien Lagrou (K)

Department of Microbiology and Immunology, KU Leuven, 3000, Leuven, Belgium.
Department of Laboratory Medicine, UZ Leuven, 3000, Leuven, Belgium.
ORCID: 0000-0001-8668-1350

Johan Maertens (J)

Department of Hematology, UZ Leuven, 3000, Leuven, Belgium.
Department of Microbiology and Immunology, KU Leuven, 3000, Leuven, Belgium.

João F Lacerda (JF)

Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, 1649-028, Lisboa, Portugal.

António Campos (A)

STMO, Instituto Português de Oncologia, 4200-072, Porto, Portugal.

Gordon D Brown (GD)

MRC Centre for Medical Mycology, University of Aberdeen, Aberdeen, AB25 2ZD, UK.

Axel A Brakhage (AA)

Department of Molecular and Applied Microbiology, Leibniz-Institute for Natural Product Research and Infection Biology, 07745, Jena, Germany.
Institute of Microbiology, Friedrich Schiller University, 07743, Jena, Germany.

Coral Barbas (C)

Center for Metabolomics and Bioanalysis, Faculty of Pharmacy, San Pablo CEU University, 28668, Madrid, Spain.
ORCID: 0000-0003-4722-491X

Ricardo Silvestre (R)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.
ORCID: 0000-0002-9270-2717

Frank L van de Veerdonk (FL)

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Centre, 6500HB, Nijmegen, Netherlands.

Georgios Chamilos (G)

School of Medicine, University of Crete, 70013, Heraklion, Greece.
Institute of Molecular Biology and Biotechnology, FORTH, 70013, Heraklion, Greece.

Mihai G Netea (MG)

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Centre, 6500HB, Nijmegen, Netherlands.
Department of Genomics & Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115, Bonn, Germany.
ORCID: 0000-0003-2421-6052

Jean-Paul Latgé (JP)

Unité des Aspergillus, Institut Pasteur, 75015, Paris, France.
ORCID: 0000-0001-6987-4417

Cristina Cunha (C)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal.
ORCID: 0000-0002-6002-5782

Agostinho Carvalho (A)

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal. agostinhocarvalho@med.uminho.pt.
ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal. agostinhocarvalho@med.uminho.pt.
ORCID: 0000-0001-8935-8030

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Eucaryotes › Champignons › Deuteromycota › Aspergillus › Aspergillus fumigatus › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Systèmes de seconds messagers › Signalisation calcique › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Glucides › Sucres › Oses › Hexose › Glucose › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Métabolisme › Voies et réseaux métaboliques › Glycolyse › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique hélice-boucle-hélice › Facteur-1 induit par l'hypoxie › Sous-unité alpha du facteur-1 induit par l'hypoxie › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunité › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Composés chimiques organiques › Acides carboxyliques › Hydroxyacides › Lactates › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Phagocytes › Macrophages › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Facteurs biologiques › Pigments biologiques › Mélanines › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Vésicules cytoplasmiques › Phagosomes › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Phagosomal removal of fungal melanin...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Transcriptome › Phagosomal removal of fungal melanin...