Abstract
Like viruses, intracellular bacteria stimulate their host cells to produce type I IFNs (IFN-alpha and IFN-beta). In our study, we investigated the signals and molecules relevant for the synthesis of and response to IFN by mouse macrophages infected with Listeria monocytogenes. We report that IFN-beta is the critical immediate-early IFN made during infection, because the synthesis of all other type I IFN, expression of a subset of infection-induced genes, and the biological response to type I IFN was lost upon IFN-beta deficiency. The induction of IFN-beta mRNA and the IFN-beta-dependent sensitization of macrophages to bacteria-induced death, in turn, was absolutely dependent upon the presence of the transcription factor IFN regulatory factor 3 (IRF3). IFN-beta synthesis and signal transduction occurred in macrophages deficient for TLR or their adaptors MyD88, TRIF, or TRAM. Expression of Nod2, a candidate receptor for intracellular bacteria, increased during infection, but the protein was not required for Listeria-induced signal transduction to the Ifn-beta gene. Based on our data, we propose that IRF3 is a convergence point for signals derived from structurally unrelated intracellular pathogens, and that L. monocytogenes stimulates a novel TLR- and Nod2-independent pathway to target IRF3 and the type I IFN genes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport / deficiency
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Animals
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Antigens, Differentiation
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Cells, Cultured
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Gene Expression Regulation / immunology*
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Humans
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Interferon Regulatory Factor-3
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Interferon-alpha / biosynthesis
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Interferon-alpha / physiology
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Interferon-beta / biosynthesis*
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Interferon-beta / deficiency
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Interferon-beta / genetics
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Interferon-beta / physiology
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Intracellular Fluid / immunology*
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Intracellular Fluid / metabolism
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Intracellular Fluid / microbiology*
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / physiology*
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Listeria monocytogenes / immunology
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / microbiology
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Membrane Proteins / deficiency
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Differentiation Factor 88
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Nod2 Signaling Adaptor Protein
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Protein Isoforms / biosynthesis
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Protein Isoforms / physiology
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / physiology*
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Receptors, Immunologic / deficiency
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Signal Transduction / genetics
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Signal Transduction / immunology
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Toll-Like Receptors
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Antigens, Differentiation
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DNA-Binding Proteins
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Interferon-alpha
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Intracellular Signaling Peptides and Proteins
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Irf3 protein, mouse
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MYD88 protein, human
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Membrane Glycoproteins
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Membrane Proteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NOD2 protein, human
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Nod2 Signaling Adaptor Protein
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Nod2 protein, mouse
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Protein Isoforms
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Receptors, Cell Surface
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Receptors, Immunologic
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TICAM-1 protein, mouse
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Toll-Like Receptors
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Transcription Factors
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Trh1 protein, mouse
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Interferon-beta