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Updated: Aug 13, 2026

Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo
Published on: September 18, 2014
Recognition of cytosolic DNA activates an IRF3-dependent innate immune response
Daniel B Stetson1, Ruslan Medzhitov
1Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Abstract:
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.
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