Journal
PLOS PATHOGENS
Volume 12, Issue 2, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1005408
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Funding
- International Max Planck Research School for Infectious Diseases and Immunology (IMPRS-IDI)
- German Research Foundation (DFG) [SPP1580/OP86/10-1, SFB/TR84, SPP1580/HI1511/3-1]
- Medical Research Council [MC_UP_A500_1020, G1100713, MC_UU_12016/5] Funding Source: researchfish
- MRC [MC_UP_A500_1020, MC_UU_12016/5, G1100713] Funding Source: UKRI
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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.
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