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

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.

• 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.; Opitz, B.