A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity.
A conundrum of innate antiviral immunity is how nucleic acid-sensing Toll-like receptors (TLRs) and RIG-I/MDA5 receptors cooperate during virus infection. The conventional wisdom has been that the activation of these receptor pathways evokes type I IFN (IFN) responses. Here, we provide evidence for a critical role of a Toll-like receptor 3 (TLR3)-dependent type II IFN signaling pathway in antiviral innate immune response against Coxsackievirus group B serotype 3 (CVB3), a member of the positive-stranded RNA virus family picornaviridae and most prevalent virus associated with chronic dilated cardiomyopathy. TLR3-deficient mice show a vulnerability to CVB3, accompanied by acute myocarditis, whereas transgenic expression of TLR3 endows even type I IFN signal-deficient mice resistance to CVB3 and other types of viruses, provided that type II IFN signaling remains intact. Taken together, our results indicate a critical cooperation of the RIG-I/MDA5-type I IFN and the TLR3-type II IFN signaling axes for efficient innate antiviral immune responses.
Negishi
Hideo
H
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Osawa
Tomoko
T
Ogami
Kentaro
K
Ouyang
Xinshou
X
Sakaguchi
Shinya
S
Koshiba
Ryuji
R
Yanai
Hideyuki
H
Seko
Yoshinori
Y
Shitara
Hiroshi
H
Bishop
Keith
K
Yonekawa
Hiromichi
H
Tamura
Tomohiko
T
Kaisho
Tsuneyasu
T
Taya
Choji
C
Taniguchi
Tadatsugu
T
Honda
Kenya
K
D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004770:Enterovirus / Q000276:immunology; D007113:Immunity, Innate; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology / Q000821:virology; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology*
D007370:Interferon Type I; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D007371:Interferon-gamma; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1