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

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

doi:10.1371/journal.ppat.1005408

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.

Highlights

Intracellular bacteria are major causes of morbidity and mortality
Numerous intracellular bacterial pathogens replicate in specialized vacuoles within macrophages
Using L. pneumophila, an important cause of pneumonia and model organism for intracellular bacteria, we found that type I and II interferons critically modify the proteome of bacterial vacuoles to restrict infection

Summary

Introduction

Intracellular bacteria are major causes of morbidity and mortality. Many intracellular pathogens establish intracellular membrane-bound compartments, where they resist lysosomal degradation and humoral immune responses [1]. As a result of co-evolution, host cells have in turn developed strategies to target the vacuoles or the bacteria inside in order to control infections [2,3]. Interferons (IFNs), which are classified into type I, II and III IFNs [4], are potent inducers of intracellular immunity in vertebrates [2]. They fulfill this function by activating transcription of partly overlapping sets of so-called IFN-stimulated genes (ISGs), several of which with antiviral or antibacterial activities. The exact functions of many ISGs remain unknown [2]

Methods

Results

Discussion

Conclusion