title: IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid.
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.
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Naujoks
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Tabeling
authors.affiliation: MRC Protein Phosphorylation Unit, University of Dundee, Dundee, United Kingdom.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dill
authors.affiliation: Max-von-Pettenkofer Institute, Ludwig Maximilian University, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: The Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Brown
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Kunze
authors.affiliation: Integrative Metabolomics and Proteomics, Institute of Medical Systems Biology/Max-Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kempa
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Peter
authors.affiliation: Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.affiliation: Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Anca
authors.initials: A
authors.lastname: Dorhoi
authors.affiliation: Department of Veterinary Pathology, Free University Berlin, Berlin, Germany.
authors.forename: Olivia
authors.initials: O
authors.lastname: Kershaw
authors.affiliation: Department of Veterinary Pathology, Free University Berlin, Berlin, Germany.
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Leif E
authors.initials: LE
authors.lastname: Sander
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.affiliation: Medizinische Klinik II, University Giessen and Marburg Lung Center, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Nerlich
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Hocke
authors.affiliation: The Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: van Driel
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.affiliation: The Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia.
authors.forename: Sammy
authors.initials: S
authors.lastname: Bedoui
authors.affiliation: Max-von-Pettenkofer Institute, Ludwig Maximilian University, Munich, Germany.|Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hilbi
authors.affiliation: MRC Protein Phosphorylation Unit, University of Dundee, Dundee, United Kingdom.
authors.forename: Matthias
authors.initials: M
authors.lastname: Trost
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Opitz
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D063990:Gene Ontology; D006836:Hydro-Lyases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate; D007372:Interferons / Q000276:immunology* / Q000378:metabolism; D016952:Legionella pneumophila / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007877:Legionnaires' Disease / Q000276:immunology* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D018448:Models, Immunological; D020543:Proteome; D017382:Reactive Oxygen Species / Q000378:metabolism; D013386:Succinates / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism / Q000382:microbiology
chemical_list: D020543:Proteome; D017382:Reactive Oxygen Species; D013386:Succinates; D007372:Interferons; D006836:Hydro-Lyases; C487648:Acod1 protein, mouse; C005229:itaconic acid
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