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Quantitative omics reveals that type I and II IFNs alter bacterial vacuole compositions to restrict infection in macrophages and lungs

ABSTRACT: The innate defense mechanisms that control infections with intracellular bacteria are still incompletely understood. Here we show that type I and II IFNs are key regulators of the early gene expression and the host-protective immune response during Legionella pneumophila-induced pneumonia. Using mixed bone marrow-chimeric mice and isolated cells we indicate that both IFNs protect against L. pneumophila by activating an alveolar macrophage-intrinsic antibacterial defense pathway. Quantitative mass spectrometry analysis reveals that both IFNs markedly alter the protein composition of purified Legionella-containing vacuoles, and integrated network analysis defines distinct subsets of IFN-regulated proteins. Subsequent experiments uncover Immunoresponsive gene 1 (Irg1) as a central effector that restricts the bacteria through production of itaconic acid. Collectively, we provide a comprehensive analysis of IFN-mediated effects on gene expression and the bacterial vacuole proteome, and show that L. pneumophila is restricted by an Irg1-dependent production of a bactericidal metabolite. Microarray experiments were performed as dual-color hybridizations on Agilent mouse whole genome catalog 44K arrays. To compensate for dye-specific effects, a dye-reversal color-swap was applied.

ORGANISM(S): Mus musculus

SUBMITTER: Hans-Joachim Mollenkopf

PROVIDER: E-GEOD-60085 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Quantitative omics reveals that type I and II IFNs alter bacterial vacuole compositions to restrict infection in macrophages and lungs

Project description:The innate defense mechanisms that control infections with intracellular bacteria are still incompletely understood. Here we show that type I and II IFNs are key regulators of the early gene expression and the host-protective immune response during Legionella pneumophila-induced pneumonia. Using mixed bone marrow-chimeric mice and isolated cells we indicate that both IFNs protect against L. pneumophila by activating an alveolar macrophage-intrinsic antibacterial defense pathway. Quantitative mass spectrometry analysis reveals that both IFNs markedly alter the protein composition of purified Legionella-containing vacuoles, and integrated network analysis defines distinct subsets of IFN-regulated proteins. Subsequent experiments uncover Immunoresponsive gene 1 (Irg1) as a central effector that restricts the bacteria through production of itaconic acid. Collectively, we provide a comprehensive analysis of IFN-mediated effects on gene expression and the bacterial vacuole proteome, and show that L. pneumophila is restricted by an Irg1-dependent production of a bactericidal metabolite.

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