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Naujoks, Jan; Tabeling, Christoph; Dill, Brian D.; Hoffmann, Christine; Brown, Andrew S.; Kunze, Mareike; Kempa, Stefan; Peter, Andrea; Mollenkopf, Hans-Joachim; Dorhoi, Anca; Kershaw, Olivia; Gruber, Achim D.; Sander, Leif E.; Witzenrath, Martin; Herold, Susanne; Nerlich, Andreas; Hocke, Andreas C.; Driel, Ian van; Suttorp, Norbert; Bedoui, Sammy; Hilbi, Hubert; Trost, Matthias; Opitz, Bastian (2016): IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid.
In: PLOS Pathogens 12(2), e1005408
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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.