PLoS Pathogens (Feb 2016)

IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid.

  • Jan Naujoks,
  • Christoph Tabeling,
  • Brian D Dill,
  • Christine Hoffmann,
  • Andrew S Brown,
  • Mareike Kunze,
  • Stefan Kempa,
  • Andrea Peter,
  • Hans-Joachim Mollenkopf,
  • Anca Dorhoi,
  • Olivia Kershaw,
  • Achim D Gruber,
  • Leif E Sander,
  • Martin Witzenrath,
  • Susanne Herold,
  • Andreas Nerlich,
  • Andreas C Hocke,
  • Ian van Driel,
  • Norbert Suttorp,
  • Sammy Bedoui,
  • Hubert Hilbi,
  • Matthias Trost,
  • Bastian Opitz

DOI
https://doi.org/10.1371/journal.ppat.1005408
Journal volume & issue
Vol. 12, no. 2
p. e1005408

Abstract

Read online

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.