A Toll-like receptor–independent antiviral response induced by double-stranded B-form DNA

Ken J Ishii^1, 2, Cevayir Coban^2, 3, Hiroki Kato², Ken Takahashi², Yuichi Torii², Fumihiko Takeshita⁴, Holger Ludwig⁵, Gerd Sutter⁵, Koichi Suzuki⁶, Hiroaki Hemmi², Shintaro Sato², Masahiro Yamamoto², Satoshi Uematsu², Taro Kawai^1, 2, Osamu Takeuchi^1, 2 & Shizuo Akira^1, 2, 3

¹  Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.

²  Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.

³  The 21st Century COE, Combined Program on Microbiology and Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.

⁴  Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.

⁵  Abteilung fur Virologie, Paul-Ehrlich Institut, 63225 Langen, Germany.

⁶  Department of Host Defense, Leprosy Research Center, National Institute of Infectious Diseases, Tokyo 189-0002, Japan.

The innate immune system recognizes nucleic acids during infection or tissue damage; however, the mechanisms of intracellular recognition of DNA have not been fully elucidated. Here we show that intracellular administration of double-stranded B-form DNA (B-DNA) triggered antiviral responses including production of type I interferons and chemokines independently of Toll-like receptors or the helicase RIG-I. B-DNA activated transcription factor IRF3 and the promoter of the gene encoding interferon- through a signaling pathway that required the kinases TBK1 and IKKi, whereas there was substantial activation of transcription factor NF-B independent of both TBK and IKKi. IPS-1, an adaptor molecule linking RIG-I and TBK1, was involved in B-DNA-induced activation of interferon- and NF-B. B-DNA signaling by this pathway conferred resistance to viral infection in a way dependent on both TBK1 and IKKi. These results suggest that both TBK1 and IKKi are required for innate immune activation by B-DNA, which might be important in antiviral innate immunity and other DNA-associated immune disorders.

	Top