Recognition of Cytosolic DNA Activates an IRF3-Dependent Innate Immune Response

• Published in: Immunity (Cambridge, Mass.) Vol. 24; no. 1; pp. 93 - 103
• Main Authors: Stetson, Daniel B., Medzhitov, Ruslan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2006; Elsevier Limited
• Subjects: Animals; Bacteria; Base Sequence; Cytosol - chemistry; Deoxyribonucleic acid; DNA; DNA, Bacterial - analysis; DNA, Bacterial - chemistry; DNA, Bacterial - immunology; Gene Expression; Immune system; Immunity, Innate - genetics; Infections; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Interferon-beta - genetics; Interferon-beta - metabolism; Kinases; Legionella pneumophila; Legionella pneumophila - genetics; Legionella pneumophila - immunology; Ligands; Listeria; Listeria monocytogenes; Listeria monocytogenes - genetics; Listeria monocytogenes - immunology; Mice; Mice, Mutant Strains; Mitogen-Activated Protein Kinase Kinases - metabolism; NF-kappa B - metabolism; Oligonucleotide Array Sequence Analysis; Proteins; Sugar Phosphates - analysis; Sugar Phosphates - immunology; Viral infections
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2005.12.003

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-κB 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.