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

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    Author
    Naujoks, J; Tabeling, C; Dill, BD; Hoffmann, C; Brown, AS; Kunze, M; Kempa, S; Peter, A; Mollenkopf, H-J; Dorhoi, A; ...
    Date
    2016-02-01
    Source Title
    PLoS Pathogens
    Publisher
    PUBLIC LIBRARY SCIENCE
    University of Melbourne Author/s
    Bedoui, Sammy; BROWN, ANDREW; van Driel, Ian
    Affiliation
    Microbiology and Immunology
    School of Biomedical Sciences
    Biochemistry and Molecular Biology
    Metadata
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    Document Type
    Journal Article
    Citations
    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. ,... Opitz, B. (2016). IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid. PLOS PATHOGENS, 12 (2), https://doi.org/10.1371/journal.ppat.1005408.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/258941
    DOI
    10.1371/journal.ppat.1005408
    Abstract
    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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