IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid

被引：215

作者：

Naujoks, Jan ^{[1
]}

Tabeling, Christoph ^{[1
]}

Dill, Brian D. ^{[2
,12
]}

Hoffmann, Christine ^{[3
]}

Brown, Andrew S. ^{[4
]}

Kunze, Mareike ^{[1
]}

Kempa, Stefan ^{[5
]}

Peter, Andrea ^{[1
]}

Mollenkopf, Hans-Joachim ^{[6
]}

Dorhoi, Anca ^{[6
]}

Kershaw, Olivia ^{[7
]}

Gruber, Achim D. ^{[7
]}

Sander, Leif E. ^{[1
]}

Witzenrath, Martin ^{[1
]}

Herold, Susanne ^{[8
,9
]}

Nerlich, Andreas ^{[1
]}

Hocke, Andreas C. ^{[1
]}

van Driel, Ian ^{[4
]}

Suttorp, Norbert ^{[1
]}

Bedoui, Sammy ^{[10
]}

Hilbi, Hubert ^{[3
,11
]}

Trost, Matthias ^{[2
]}

Opitz, Bastian ^{[1
]}

机构：

[1] Charite, Dept Internal Med Infect Dis & Pulm Med, D-13353 Berlin, Germany

[2] Univ Dundee, MRC Prot Phosphorylat Unit, Dundee, Scotland

[3] Univ Munich, Max Von Pettenkofer Inst, Munich, Germany

[4] Univ Melbourne, Dept Biochem & Mol Biol, Melbourne, Vic, Australia

[5] Max Delbruck Ctr Mol Med, Integrat Metab & Prote, Inst Med Syst Biol, Berlin, Germany

[6] Max Planck Inst Infect Biol, Berlin, Germany

[7] Free Univ Berlin, Dept Vet Pathol, Berlin, Germany

[8] Univ Giessen, Med Klin 2, D-35390 Giessen, Germany

[9] Univ Giessen, Marburg Lung Ctr, D-35390 Giessen, Germany

[10] Univ Melbourne, Dept Microbiol & Immunol, Melbourne, Vic, Australia

[11] Univ Zurich, Inst Med Microbiol, Zurich, Switzerland

[12] Rockefeller Univ, Prote Resource Ctr, 1230 York Ave, New York, NY 10021 USA

来源：

PLOS PATHOGENS | 2016年 / 12卷 / 02期

关键词：

CELL-AUTONOMOUS IMMUNITY; C VIRUS-REPLICATION; PNEUMOPHILA INFECTION; TOXOPLASMA-GONDII; INTERFERON-GAMMA; INTRACELLULAR PATHOGENS; BACTERICIDAL ACTIVITY; ALVEOLAR MACROPHAGES; MITOCHONDRIAL ROS; EPITHELIAL-CELLS;

D O I：

10.1371/journal.ppat.1005408

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Macrophages can be niches for bacterial pathogens or antibacterial effector cells depending on the pathogen and signals from the immune system. Here we show that type I and II IFNs are master regulators of gene expression during Legionella pneumophila infection, and activators of an alveolar macrophage-intrinsic immune response that restricts bacterial growth during pneumonia. Quantitative mass spectrometry revealed that both IFNs substantially modify Legionella-containing vacuoles, and comparative analyses reveal distinct subsets of transcriptionally and spatially IFN-regulated proteins. Immune-responsive gene (IRG) 1 is induced by IFNs in mitochondria that closely associate with Legionella-containing vacuoles, and mediates production of itaconic acid. This metabolite is bactericidal against intravacuolar L. pneumophila as well as extracellular multidrug-resistant Gram-positive and -negative bacteria. Our study explores the overall role IFNs play in inducing substantial remodeling of bacterial vacuoles and in stimulating production of IRG1-derived itaconic acid which targets intravacuolar pathogens. IRG1 or its product itaconic acid might be therapeutically targetable to fight intracellular and drug-resistant bacteria.

引用

页数：27

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