IFN regulatory factor 3-dependent induction of type I IFNs by intracellular bacteria is mediated by a TLR- and Nod2-independent mechanism.
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.
Stockinger
Silvia
S
Max F. Perutz Laboratories, University Department at the Vienna Biocenter, Department of Microbiology and Genetics, University of Vienna, Austria.
Reutterer
Benjamin
B
Schaljo
Barbara
B
Schellack
Carola
C
Brunner
Sylvia
S
Materna
Tilo
T
Yamamoto
Masahiro
M
Akira
Shizuo
S
Taniguchi
Tadatsugu
T
Murray
Peter J
PJ
Müller
Mathias
M
Decker
Thomas
T
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency; D000818:Animals; D000943:Antigens, Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha / Q000096:biosynthesis / Q000502:physiology; D016899:Interferon-beta / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007424:Intracellular Fluid / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008089:Listeria monocytogenes / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D053473:Nod2 Signaling Adaptor Protein; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000172:deficiency; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051049:Sphingosine N-Acyltransferase
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D016899:Interferon-beta; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D053473:Nod2 Signaling Adaptor Protein; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D014157:Transcription Factors; C494232:IRF3 protein, human; C494233:Irf3 protein, mouse; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C429018:NOD2 protein, human; C495945:Nod2 protein, mouse; C476286:Ticam1 protein, mouse; C000599817:CERS4 protein, mouse; D051049:Sphingosine N-Acyltransferase