School of Biomedical Sciences - Research Publications

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Author: Bedoui, Sammy × Author: BROWN, ANDREW × Start date: 2015 ×

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    IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid
    Naujoks, J ; Tabeling, C ; Dill, BD ; Hoffmann, C ; Brown, AS ; Kunze, M ; Kempa, S ; Peter, A ; Mollenkopf, H-J ; Dorhoi, A ; Kershaw, O ; Gruber, AD ; Sander, LE ; Witzenrath, M ; Herold, S ; Nerlich, A ; Hocke, AC ; van Driel, I ; Suttorp, N ; Bedoui, S ; Hilbi, H ; Trost, M ; Opitz, B ; Zamboni, DS (PUBLIC LIBRARY SCIENCE, 2016-02)
    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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    Differential use of autophagy by primary dendritic cells specialized in cross-presentation
    Mintern, JD ; Macri, C ; Chin, WJ ; Panozza, SE ; Segura, E ; Patterson, NL ; Zeller, P ; Bourges, D ; Bedoui, S ; McMillan, PJ ; Idris, A ; Nowell, CJ ; Brown, A ; Radford, KJ ; Johnston, APR ; Villadangos, JA (TAYLOR & FRANCIS INC, 2015-06)
    Antigen-presenting cells survey their environment and present captured antigens bound to major histocompatibility complex (MHC) molecules. Formation of MHC-antigen complexes occurs in specialized compartments where multiple protein trafficking routes, still incompletely understood, converge. Autophagy is a route that enables the presentation of cytosolic antigen by MHC class II molecules. Some reports also implicate autophagy in the presentation of extracellular, endocytosed antigen by MHC class I molecules, a pathway termed "cross-presentation." The role of autophagy in cross-presentation is controversial. This may be due to studies using different types of antigen presenting cells for which the use of autophagy is not well defined. Here we report that active use of autophagy is evident only in DC subtypes specialized in cross-presentation. However, the contribution of autophagy to cross-presentation varied depending on the form of antigen: it was negligible in the case of cell-associated antigen or antigen delivered via receptor-mediated endocytosis, but more prominent when the antigen was a soluble protein. These findings highlight the differential use of autophagy and its machinery by primary cells equipped with specific immune function, and prompt careful reassessment of the participation of this endocytic pathway in antigen cross-presentation.