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

被引：84

作者：

Goncalves, Samuel M. ^{[1
,2
]}

Duarte-Oliveira, Claudio ^{[1
,2
]}

Campos, Claudia F. ^{[1
,2
]}

Aimanianda, Vishukumar ^{[3
]}

ter Horst, Rob ^{[4
,5
]}

Leite, Luis ^{[6
]}

Mercier, Toine ^{[7
,8
]}

Pereira, Paulo ^{[9
]}

Fernandez-Garcia, Miguel ^{[10
]}

Antunes, Daniela ^{[1
,2
]}

Rodrigues, Claudia S. ^{[1
,2
]}

Barbosa-Matos, Catarina ^{[1
,2
]}

Gaifem, Joana ^{[1
,2
]}

Mesquita, Ines ^{[1
,2
]}

Marques, Antonio ^{[11
]}

Osorio, Nuno S. ^{[1
,2
]}

Torrado, Egidio ^{[1
,2
]}

Rodrigues, Fernando ^{[1
,2
]}

Costa, Sandra ^{[1
,2
]}

Joosten, Leo A. B. ^{[4
,5
]}

Lagrou, Katrien ^{[8
,12
]}

Maertens, Johan ^{[7
,8
]}

Lacerda, Joao F. ^{[9
]}

Campos Jr, Antonio ^{[6
]}

Brown, Gordon D. ^{[13
]}

Brakhage, Axel A. ^{[14
,15
]}

Barbas, Coral ^{[10
]}

Silvestre, Ricardo ^{[1
,2
]}

van de Veerdonk, Frank L. ^{[4
,5
]}

Chamilos, Georgios ^{[16
,17
]}

Netea, Mihai G. ^{[4
,5
,18
]}

Latge, Jean-Paul ^{[3
]}

Cunha, Cristina ^{[1
,2
]}

Carvalho, Agostinho ^{[1
,2
]}

机构：

[1] Univ Minho, Sch Med, Life & Hlth Sci Res Inst ICVS, P-4710057 Braga, Portugal

[2] ICVS 3Bs PT Govt Associate Lab, Guimaraes Braga, Portugal

[3] Inst Pasteur, Unite Aspergillus, F-75015 Paris, France

[4] Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, NL-6500 HB Nijmegen, Netherlands

[5] Radboud Univ Nijmegen, Radboud Ctr Infect Dis, Med Ctr, NL-6500 HB Nijmegen, Netherlands

[6] Inst Portugues Oncol Francisco Gentil, STMO, P-4200072 Porto, Portugal

[7] UZ Leuven, Dept Hematol, B-3000 Leuven, Belgium

[8] Katholieke Univ Leuven, Dept Microbiol & Immunol, B-3000 Leuven, Belgium

[9] Inst Med Mol, Fac Med Lisboa, P-1649028 Lisbon, Portugal

[10] San Pablo CEU Univ, Fac Pharm, Ctr Metabol & Bioanal, Madrid 28668, Spain

[11] Hosp Braga, Serv Imunohemoterapia, P-4710243 Braga, Portugal

[12] UZ Leuven, Dept Lab Med, B-3000 Leuven, Belgium

[13] Univ Aberdeen, Ctr Med Mycol, MRC, Aberdeen AB25 2ZD, Scotland

[14] Leibniz Inst Nat Prod Res & Infect Biol, Dept Mol & Appl Microbiol, D-07745 Jena, Germany

[15] Friedrich Schiller Univ, Inst Microbiol, D-07743 Jena, Germany

[16] Univ Crete, Sch Med, Iraklion 70013, Greece

[17] FORTH, Inst Mol Biol & Biotechnol, Iraklion 70013, Greece

[18] Univ Bonn, Life & Med Sci Inst, Dept Genom & Immunoregulat, D-53115 Bonn, Germany

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

ASPERGILLUS-FUMIGATUS; SUCCINATE-DEHYDROGENASE; CELLULAR-METABOLISM; DENDRITIC CELL; MTOR; BIOSYNTHESIS; PHAGOCYTOSIS; ACTIVATION; INHIBITION; CONIDIA;

D O I：

10.1038/s41467-020-16120-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-1 alpha) 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. Macrophages undergo a Warburg-like switch from oxidative phosphorylation to glycolysis in response to inflammatory stimulus. Here the authors show that fungal melanin can trigger this switch in human macrophages by sequestering calcium in the phagosome and enabling protection against Aspergillus fumigatus infection.

引用

页数：15

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