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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, etc.

PLoS Pathog. 2016 Feb 1;12(2):e1005408.

PMID: 26829557

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.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
AP97654 Itaconic acid Itaconic acid 97-65-4 Price
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