School of Biomedical Sciences - Research Publications

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Author: Bedoui, Sammy × Author: van Driel, Ian × Author: BROWN, ANDREW × Start date: 2016 × End date: 2016 ×

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    IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid
    Naujoks, J ; Tabeling, C ; Dill, BD ; Hoffmann, C ; Brown, AS ; Kunze, M ; Kempa, S ; Peter, A ; Mollenkopf, H-J ; Dorhoi, A ; Kershaw, O ; Gruber, AD ; Sander, LE ; Witzenrath, M ; Herold, S ; Nerlich, A ; Hocke, AC ; van Driel, I ; Suttorp, N ; Bedoui, S ; Hilbi, H ; Trost, M ; Opitz, B ; Zamboni, DS (PUBLIC LIBRARY SCIENCE, 2016-02)
    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.