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IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid
Open accessAbstract
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.
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“The therapeutic potential of DI was also demonstrated as in vivo administration of DI resulted in an amelioration of skin pathology in a mouse model of psoriasis, a disease also currently treated by the related electrophile DMF60,65.”
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Metadata
- Authors
- Naujoks, J., Tabeling, C., Dill, B. D., Hoffmann, C., Brown, A. S., Kunze, M., Kempa, S., Peter, A., Mollenkopf, H.-J., Dorhoi, A., Kershaw, O., Gruber, A. D., Sander, L. E., Witzenrath, M., Herold, S., Nerlich, A., Hocke, A. C., van Driel, I., Suttorp, N., Bedoui, S., Hilbi, H., Trost, M., & Opitz, B.
- Affiliations
- Charité – Universitätsmedizin Berlin (DE)
- University of Dundee (GB)
- Max-von-Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie (DE)
- The University of Melbourne (AU)
- Max Delbrück Center (DE)
- Max Planck Institute for Infection Biology (DE)
- Freie Universität Berlin (DE)
- Justus-Liebig-Universität Gießen (DE)
- University of Zurich (CH)
- Corresponding author
- Opitz, Bastian
- ORCID
- Venue
- PLOS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-02-01
- Volume
- 12
- Issue
- 2
- Pages
- e1005408
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC4734697
- OpenAlex
- W2270624586
- Cited by
- 261
- References
- 71
- Citations by year
- 2026: 17 · 2025: 30 · 2024: 24 · 2023: 19 · 2022: 34 · 2021: 33 · 2020: 25 · 2019: 27 · 2018: 22 · 2017: 20 · 2016: 10
- FWCI
- 25.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, cc-by)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- International Max Planck Research School for Environmental, Cellular and Molecular Microbiology
- Deutsche Forschungsgemeinschaft (SPP1580/OP86/10-1, SPP 1580, SFB‐TR84)
- International Max Planck Research School for Advanced Methods in Process and Systems Engineering
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Legionella and Acanthamoeba research
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- type I interferon, interferon-gamma, Legionella pneumophila, Legionnaires' disease, Legionella-containing vacuole, IRG1, itaconic acid, alveolar macrophages, intracellular bacterial infection, antimicrobial metabolites, multidrug-resistant bacteria, host-pathogen interaction, innate immunity
- MeSH terms
- Animals, Disease Models, Animal, Female, Gene Expression Regulation, Hydro-Lyases, Immunity, Innate, Interferons, Legionnaires' Disease, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Succinates, Vacuoles, Macrophages, Alveolar, Legionella pneumophila, Reactive Oxygen Species, Models, Immunological, Proteome, Mice, Gene Ontology
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