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