folder

IFNs modify the proteome of Legionella-containing vacuoles and restrict infection via IRG1-derived itaconic acid

Authors

  • J. Naujoks
  • C. Tabeling
  • B.D. Dill
  • C. Hoffmann
  • A.S. Brown
  • M. Kunze
  • S. Kempa
  • A. Peter
  • H.J. Mollenkopf
  • A. Dorhoi
  • O. Kershaw
  • A.D. Gruber
  • L.E. Sander
  • M. Witzenrath
  • S. Herold
  • A. Nerlich
  • A.C. Hocke
  • I. van Driel
  • N. Suttorp
  • S. Bedoui
  • H. Hilbi
  • M. Trost
  • B. Opitz

Journal

  • PLoS Pathogens

Citation

  • PLoS Pathog 12 (2): e1005408

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.


DOI

doi:10.1371/journal.ppat.1005408