Recognition of cytosolic DNA activates an IRF3-dependent innate immune response.
Nucleic acid recognition upon viral infection triggers type I interferon production. Viral RNA is detected by both endosomal, TLR-dependent and cytosolic, RIG-I/MDA5-dependent pathways. TLR9 is the only known sensor of foreign DNA; it is unknown whether innate immune recognition of DNA exists in the cytosol. Here we present evidence that cytosolic DNA activates a potent type I interferon response to the invasive bacterium Listeria monocytogenes. The noninvasive Legionella pneumophila triggers an identical response through its type IV secretion system. Activation of type I interferons by cytosolic DNA is TLR independent and requires IRF3 but occurs without detectable activation of NF-kappaB and MAP kinases. Microarray analyses reveal a unique but overlapping gene-expression program activated by cytosolic DNA compared to TLR9- and RIG-I/MDA5-dependent responses. These findings define an innate immune response to DNA linked to type I interferon production.
Stetson
Daniel B
DB
Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Medzhitov
Ruslan
R
D000818:Animals; D001483:Base Sequence; D003600:Cytosol / Q000737:chemistry; D004269:DNA, Bacterial / Q000032:analysis / Q000737:chemistry / Q000276:immunology*; D015870:Gene Expression; D007113:Immunity, Innate / Q000235:genetics; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D016952:Legionella pneumophila / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D013403:Sugar Phosphates / Q000032:analysis / Q000276:immunology
D004269:DNA, Bacterial; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008024:Ligands; D016328:NF-kappa B; D013403:Sugar Phosphates; D016899:Interferon-beta; D020929:Mitogen-Activated Protein Kinase Kinases