IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid.
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 macroph...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-02-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1005408 |
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| author | Jan Naujoks Christoph Tabeling Brian D Dill Christine Hoffmann Andrew S Brown Mareike Kunze Stefan Kempa Andrea Peter Hans-Joachim Mollenkopf Anca Dorhoi Olivia Kershaw Achim D Gruber Leif E Sander Martin Witzenrath Susanne Herold Andreas Nerlich Andreas C Hocke Ian van Driel Norbert Suttorp Sammy Bedoui Hubert Hilbi Matthias Trost Bastian Opitz |
| author_facet | Jan Naujoks Christoph Tabeling Brian D Dill Christine Hoffmann Andrew S Brown Mareike Kunze Stefan Kempa Andrea Peter Hans-Joachim Mollenkopf Anca Dorhoi Olivia Kershaw Achim D Gruber Leif E Sander Martin Witzenrath Susanne Herold Andreas Nerlich Andreas C Hocke Ian van Driel Norbert Suttorp Sammy Bedoui Hubert Hilbi Matthias Trost Bastian Opitz |
| author_sort | Jan Naujoks |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-eaa236391a7d4f88ad687cf6bf355f63 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2016-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-eaa236391a7d4f88ad687cf6bf355f632025-08-20T02:34:06ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742016-02-01122e100540810.1371/journal.ppat.1005408IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid.Jan NaujoksChristoph TabelingBrian D DillChristine HoffmannAndrew S BrownMareike KunzeStefan KempaAndrea PeterHans-Joachim MollenkopfAnca DorhoiOlivia KershawAchim D GruberLeif E SanderMartin WitzenrathSusanne HeroldAndreas NerlichAndreas C HockeIan van DrielNorbert SuttorpSammy BedouiHubert HilbiMatthias TrostBastian OpitzMacrophages 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.https://doi.org/10.1371/journal.ppat.1005408 |
| spellingShingle | Jan Naujoks Christoph Tabeling Brian D Dill Christine Hoffmann Andrew S Brown Mareike Kunze Stefan Kempa Andrea Peter Hans-Joachim Mollenkopf Anca Dorhoi Olivia Kershaw Achim D Gruber Leif E Sander Martin Witzenrath Susanne Herold Andreas Nerlich Andreas C Hocke Ian van Driel Norbert Suttorp Sammy Bedoui Hubert Hilbi Matthias Trost Bastian Opitz IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid. PLoS Pathogens |
| title | IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid. |
| title_full | IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid. |
| title_fullStr | IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid. |
| title_full_unstemmed | IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid. |
| title_short | IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid. |
| title_sort | ifns modify the proteome of legionella containing vacuoles and restrict infection via irg1 derived itaconic acid |
| url | https://doi.org/10.1371/journal.ppat.1005408 |
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