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. 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

doi:10.1038/s41467-020-16120-z

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^* (Corresponding Author), Agostinho Carvalho^*

^*Corresponding author for this work

Applied Medicine

Research output: Contribution to journal › Article › peer-review

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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 language	English
Article number	2282
Journal	Nature Communications
Volume	11
Early online date	8 May 2020
DOIs	https://doi.org/10.1038/s41467-020-16120-z
Publication status	Published - 2020

Bibliographical note

Acknowledgements
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).

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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Cite this

Gonçalves, S. M., Duarte-Oliveira, C., Campos, C. F., Aimanianda, V., ter Horst, R., Leite, L., Mercier, T., Pereira, P., Fernández-García, M., Antunes, D., Rodrigues, C. S., Barbosa-Matos, C., Gaifem, J., Mesquita, I., Marques, A., Osório, N. S., Torrado, E., Rodrigues, F., Costa, S., ... Carvalho, A. (2020). Phagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity. Nature Communications, 11, Article 2282. https://doi.org/10.1038/s41467-020-16120-z

Gonçalves, SM, Duarte-Oliveira, C, Campos, CF, Aimanianda, V, ter Horst, R, Leite, L, Mercier, T, Pereira, P, Fernández-García, M, Antunes, D, Rodrigues, CS, Barbosa-Matos, C, Gaifem, J, Mesquita, I, Marques, A, Osório, NS, Torrado, E, Rodrigues, F, Costa, S, Joosten, LAB, Lagrou, K, Maertens, J, Lacerda, JF, Campos Jr, A, Brown, GD, Brakhage, AA, Barbas, C, Silvestre, R, van de Veerdonk, FL, Chamilos, G, Netea, MG, Latgé, J-P, Cunha, C & Carvalho, A 2020, 'Phagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity', Nature Communications, vol. 11, 2282. https://doi.org/10.1038/s41467-020-16120-z

@article{1cba49922def42baa1b845ab8c5e3412,

title = "Phagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity",

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. ",

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",

author = "Gon{\c c}alves, {Samuel M.} and Cl{\'a}udio Duarte-Oliveira and Campos, {Cl{\'a}udia F.} and Vishukumar Aimanianda and {ter Horst}, Rob and Luis Leite and Toine Mercier and Paulo Pereira and Miguel Fern{\'a}ndez-Garc{\'i}a and Daniela Antunes and Rodrigues, {Cl{\'a}udia S.} and Catarina Barbosa-Matos and Joana Gaifem and In{\^e}s Mesquita and Ant{\'o}nio Marques and Os{\'o}rio, {Nuno S.} and Eg{\'i}dio Torrado and Fernando Rodrigues and Sandra Costa and Joosten, {Leo A.B.} and Katrien Lagrou and Johan Maertens and Lacerda, {Jo{\~a}o F} and {Campos Jr}, Ant{\'o}nio and Brown, {Gordon D.} and Brakhage, {Axel A} and Coral Barbas and Ricardo Silvestre and {van de Veerdonk}, {Frank L.} and Georgios Chamilos and Netea, {Mihai G.} and Jean-Paul Latg{\'e} and Cristina Cunha and Agostinho Carvalho",

note = "Acknowledgements 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 Funda{\c c}{\~a}o para a Ci{\^e}ncia 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 M{\'e}rieux (M{\'e}rieux 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). ",

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doi = "10.1038/s41467-020-16120-z",

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AU - Gonçalves, Samuel M.

AU - Duarte-Oliveira, Cláudio

AU - Campos, Cláudia F.

AU - Aimanianda, Vishukumar

AU - ter Horst, Rob

AU - Leite, Luis

AU - Mercier, Toine

AU - Pereira, Paulo

AU - Fernández-García, Miguel

AU - Antunes, Daniela

AU - Rodrigues, Cláudia S.

AU - Barbosa-Matos, Catarina

AU - Gaifem, Joana

AU - Mesquita, Inês

AU - Marques, António

AU - Osório, Nuno S.

AU - Torrado, Egídio

AU - Rodrigues, Fernando

AU - Costa, Sandra

AU - Joosten, Leo A.B.

AU - Lagrou, Katrien

AU - Maertens, Johan

AU - Lacerda, João F

AU - Campos Jr, António

AU - Brown, Gordon D.

AU - Brakhage, Axel A

AU - Barbas, Coral

AU - Silvestre, Ricardo

AU - van de Veerdonk, Frank L.

AU - Chamilos, Georgios

AU - Netea, Mihai G.

AU - Latgé, Jean-Paul

AU - Cunha, Cristina

AU - Carvalho, Agostinho

N1 - Acknowledgements 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).

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Aspergillus

KW - melanin

KW - immunometabolism

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KW - calcium

KW - macrophage

KW - antifungal immunity

KW - invasive pulmonary aspergillosis

KW - ACTIVATION

KW - ASPERGILLUS-FUMIGATUS

KW - PHAGOCYTOSIS

KW - DENDRITIC CELL

KW - CONIDIA

KW - MTOR

KW - SUCCINATE-DEHYDROGENASE

KW - INHIBITION

KW - BIOSYNTHESIS

KW - CELLULAR-METABOLISM

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DO - 10.1038/s41467-020-16120-z

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VL - 11

JO - Nature Communications

JF - Nature Communications

M1 - 2282

ER -

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

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