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| Item Type: | Article |
|---|---|
| Title: | IFNs modify the proteome of Legionella-containing vacuoles and restrict infection via IRG1-derived itaconic acid |
| Creators Name: | Naujoks, J., Tabeling, C., Dill, B.D., Hoffmann, C., Brown, A.S., Kunze, M., Kempa, S., Peter, A., Mollenkopf, H.J., Dorhoi, A., Kershaw, O., Gruber, A.D., Sander, L.E., Witzenrath, M., Herold, S., Nerlich, A., Hocke, A.C., van Driel, I., Suttorp, N., Bedoui, S., Hilbi, H., Trost, M. and Opitz, B. |
| 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. |
| Keywords: | Alveolar Macrophages, Animal Disease Models, Gene Expression Regulation, Gene Ontology, Hydro-Lyases, Immunological Models, Inbred C57BL Mice, Innate Immunity, Interferons, Legionella pneumophila, Legionnaires' Disease, Mitochondria, Proteome, Reactive Oxygen Species, Succinates, Transgenic Mice, Vacuoles, Animals, Mice |
| Source: | PLoS Pathogens |
| ISSN: | 1553-7366 |
| Publisher: | Public Library of Science |
| Volume: | 12 |
| Number: | 2 |
| Page Range: | e1005408 |
| Date: | 1 February 2016 |
| Official Publication: | https://doi.org/10.1371/journal.ppat.1005408 |
| PubMed: | View item in PubMed |
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