56 pp.1-8 2006 1. Toll-like receptors TLRs TLR I TLR2 TLR4 TLR3 TLR7 TLR8 TLR9 TLR TLR 1 I IFN 565-0871 3-1 TEL: 06-6879-8303 FAX: 06-6879-8305 E-mail: uemattsu@biken.osaka-u.ac.jp I IFN IFN- IFN- I IFN CD40, CD80, CD86 MHC DC CD8 + T CD8 + T I IFN 1 I IFN IFNAR1 IFNAR2 Janus kinase JAK -Signal transducer and activator of transcription Stat Stat1 Stat2 Stat1 Stat2 interferon regulatory factor 9 IRF9 IFN-stimulated gene factor 3 ISGF3 3 ISRE IFN 2 2 I IFN I IFN I IFN IFN- IFN-
2 56 3 ATF-2/c-Jun NF- B IRF3 NF- B IRF3 NF- B I B I B kinase IKK I B I B NF- B IRF3 non-canonical IKK TBK1/IKKi IRF3 2 JNK/p38 ATF2/c-Jun ATF-2/c-Jun NF- B IRF3 IFN- 2 IRF7 IFN I IFN IFN- s IRF7 plasmacytoid DC: pdc ATF-2/c-Jun NF- B IRF3 IFN- IRF7 IRF7 TBK1/IKKi I IFN I IFN IRF7 IFN- IFN- IRF7 IRF7 I IFN 3 3 TLR TLR TLR LRR 1 IL- 1R Toll/IL-1R TIR 4 TLR pathogen-associated molecular patterns; AMS TLR 13 1 TLR TLR TLR4 respiratory syncytial virus RSV TLR4 C3H/HeJ RSV mouse mammary tumor virus MMTV TLR4 B 1 TLR2 I herpes simplex virus- 1: HSV-1 1 2 RNA double stranded RNA: dsrna I IFN dsrna RNA dsrna polyinosinic-polycytidylic acid poly I:C dsrna TLR3 dsrna 1 TLR3 TLR4 TLR9 TLR7 TLR9 CpG DNA CpG DNA DNA CpG DNA CpG CpG DNA TLR9 CpG DNA DNA HSV-2 TLR9 IFN- 1 R-848 TLR7 TLR7 TLR7 TLR7 TLR8 RNA single starand RNA: ssrna 1 4 TLR 1 TLR TLR3 TLR MyD88 TIR TLR Death IL-1
pp.1-8 2006 3 TLR2 MyD88 IRAK-1 MD2 TLR4 TIRA/Mal IRAK-4 TRAF6 Ub TAK1 LRR TIR TRAM TRIF TLR3 IRAK-1 IRAK-4 MyD88 Ub TLR7 TLR8 TLR9 TAK1 NEMO IKKα IκB NF-κB IKKβ RI1 IKKi TBK1 IRF3 IRF7 Ub TRAF6 IKKα NEMO IKKβ IκB NF-κB IFN-β IFN IFN-αs IFN-β IFN MyD88 MyD88 pdc TLR TLR3 TLR MyD88 TLR3,TLR4 TRIF TLR7, TLR8, TLR9 pdc I IFN Ub; ; receptor associated kinase IRAK -1 IRAK-4 IRAKs TNF receptor associated factor 6 TRAF6IKK IKK I B degradation NF- B MyD88 TNF- IL-6 IL-12 B TLR2 TLR4 MyD88 TIRA/Mal 2 TIR 2 2 MyD88 TLR I IFN TLR3 TLR4 MyD88 IFN- IFN MyD88 3 TRIF TLR4 TRIF 2 TLR4 MyD88 TRIF 4 TRAM TRAM N TLR4 TRAM TLR4 TRIF TLR3 TLR4 TRIF TBK1 IKKi TBK1 IKKi IRF3 IRF3 IFN- 2 TRAF6 TRIF NF- B TRAF6 MyD88 LS NF-kB TRIF TLR4 TRAF6 NF-kB 5 Receptor-interacting protein-1 RI1 Rip homotypic interaction motif RHIM TRIF C RI1 RI1 TRIF NF- B 5 4 pdc
4 56 dsrna DNA, DNA? RIG-I MDA-5 Helicase CARDs IS1/MAVS/VISA/CARDIF CARD? Receptor X IKKi TBK1 FADD RI1 NEMO IRF3 IRF7 IKKα IKKβ IκB NF-κB IFN-β IFN-α dsrna IS-1 CARD RIG-I MDA5 TBK1/IKKi IRF3 IRF7 I IFN IS-1 FADD/RI1 NF-kB dsdna I IFN I IFN I IFN I IFN IFN producing cells IC T pdc CD11c B220 CD11c B220 pdc 6 pdc TLR7 TLR8 TLR9 1 pdc TLR7 TLR9 MyD88 I IFN pdc IRF7 IRF7 MyD88/IRAK-4/IRAK-1/TRAF6 7 IRAK-1 MyD88 IRAK-4 NF- B IRF7 8 IRF7 TRAF6 7 pdc TLR7 TLR9 IRF7 IKK- 9 IKK- MyD88/IRAK- 4/IRAK-1/TRAF6 IRF7 5 TLR TLR TLR 1 RNA Retinoic acid-inducible gene I RIG-I dsrna 10 RIG-I C N 2 caspase-recruiting domains CARD DExD/H box RNA RIG-I RNA ATase dsrna
pp.1-8 2006 5 TLR TLRs TLR2 TLR4 I respiratory syncytial virus RSV mouse mammary tumor virus MMTV TLR3 RNA RNA oly I:C TLR7/TLR8 TLR9 RNA CpG DNA N CARD IRF3 NF- B 10 RIG-I in vitro in vivo RIG-I Vesicular stomatitis virus: VSV RIG-I RNAi Newcastle disease virus encephalomyocarditis virus: EMCV I IFN 10 RIG-I RIG-I NDV VSV I IFN RIG-I pdc NDV I IFN pdc TLR RNA I IFN RIG-I TLR 11 Melanoma differentiation-associated gene 5 MDA5; Helicard DExD/H box RNA 2 CARD 1 RIG-I MDA5 dsrna NDV VSV EMCV MDA5 V V MDA5 dsrna IFN- In vitro MDA5 RNA MDA5 in vivo RIG-I MDA5 RIG-I RNA MDA5 MDA5 EMCV RIG-I MDA5 RNA 12 dsrna poly I:C TLR3 RIG-I MDA5 poly I:C I IFN MDA5 IL-12p40 TLR3 IL-6 MDA5 TLR3 RIG-I poly I:C in vitro dsrna 12 RIG-I RNA dsrna MDA5 RNA Lgp2 RIG-I MDA5 CARD Lgp2 IFN- Lgp2 RIG-I MDA5 13,14 in vivo 3 RNA RIG-I MDA5 IKK IKK / / NF- B TBK1/IKKi IRF3 IRF7 IFN-
6 56 promoter stimulator 1 IS-1 RIG-I MDA5 15 IS-1 N CARD C IS-1 CARD RIG-I MDA5 IS-1 IFN- IFN- 4 IFN- 6 NF- B VSV IS-1 RNA-i dsrna I IFN VSV NDV I IFN IS-1 I IFN TBK1 IKKi IS-1 IS-1 FADD RI1 NF- B IS-1 RIG-I MDA5 15 3 IS-1 mitochondrial anti-viral signaling protein MAVS 16 virus-induced signaling adaptor VISA 17 CARD adaptor inducing IFN- CARDIF 18 MAVS MAVS MAVS 16 4 Vaccinia virus: VV A52R TLR TLR3 NF-kB 19,20 A52R IRAK- 2 TRAF6 VV A52R VV 20 VV A46R TIR TIR IL-1R/TLR NF- B 19,21 A46R TIR NF- B IRF3 NS3-4A C hepatitis C virus: HCV NS3-4A IRF3 NS3-4A Trif TLR3 RIG-I 22,23 Meylan Cardif NS3-4A NS3-4A Cardif NS3-4A C IRF3 NF- B Cardif 18 V MDA5 MDA5 13,24 5 DNA DNA DNA TLR9 DNaseII DNase DNaseII DNA 25 DNaseII DNA DNA TLR9 IFN- 26 dsdna 27,28 B-DNA DNA Z-DNA DNA B-DNA I IFN Z-DNA B-DNA TBK1 IKKi IRF3 IFN- NF-kB TBK1 IKKi RNAi in vitro IS-1 B-DNA TLR RIG-I MDA5 B-DNA B- DNA IFN IFN B-DNA DNA 29 TLR TLR TLR I IFN TLR 1 Akira S, Uematsu S, & Takeuchi O. : athogen recognition and innate immunity. Cell 124, 783-801, 2006. 2 Akira S, & Takeda K. : Toll-like receptor signalling.
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8 56 pp.1-8 2006 28 Ishii KJ, Suzuki K, Coban C, Takeshita F, Itoh Y, Matoba H, Kohn LD. & Klinman DM. : Genomic DNA released by dying cells induces the maturation of ACs. J Immunol 167, 2602-7, 2001. 29 Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y, Takeshita F, Ludwig H, Sutter G, Suzuki K, Hemmi H, Sato S, Yamamoto M, Uematsu S, Kawai T, Takeuchi O. & Akira S. : A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol 7, 40-48, 2006. Innate Immune recognition of viral infection Satoshi UEMATSU, Shizuo AKIRA Department of Host defense, Research Institute for Microbial Diseases, Osaka University Toll-like receptors (TLRs) are key molecules of the innate immune systems, which detect conserved structures found in a broad range of pathogens and triggers innate immune responses. A subset of TLRs recognize viral components and induce antiviral responses by producing type I interferons. Whereas TLR2 and TLR4 recognize viral components at the cell surface, TLR3, TLR7, TLR8 and TLR9 are exclusively expressed in endosomal compartments. After phagocytes internalize viruses or virus-infected apoptotic cells, viral nucleic acids are released in phagolysosomes and are recognized by these TLRs. Recent reports have shown that hosts also have a mechanism to detect replicating viruses in the cytoplasm in a TLR-independent manner. In this review, we focus on the viral recognition by innate immunity and the signaling pathways.