%0 Journal Article
%T IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid
%A Jan Naujoks&nbsp
%A Christoph Tabeling&nbsp
%A Brian D. Dill&nbsp
%A Christine Hoffmann&nbsp
%A Andrew S. Brown&nbsp
%A Mareike Kunze&nbsp
%A Stefan Kempa&nbsp
%A Andrea Peter&nbsp
%A Hans-Joachim Mollenkopf&nbsp
%A Anca Dorhoi
%J PLOS Pathogens
%D 2016
%I Public Library of Science (PLoS)
%R 10.1371/journal.ppat.1005408
%X 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.
%U http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1005408