TLR TLR2 TLR4 TLR3 TLR7 TLR8 TLR9 IFN- I IFN CD40, CD80, CD86

Transcript

1 56 pp Toll-like receptors TLRs TLR I TLR2 TLR4 TLR3 TLR7 TLR8 TLR9 TLR TLR 1 I IFN TEL: FAX: 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 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 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

3 pp 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 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

5 pp 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 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 MDA 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, , Akira S, & Takeda K. : Toll-like receptor signalling.

7 pp Nat Rev Immunol. 4, , Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, Shimada N, Ohba Y, Takaoka A, Yoshida N. & Taniguchi T. : IRF-7 is the master regulator of type-i interferon-dependent immune responses. Nature 434, 772-7, Akira S. : Toll receptor families: structure and function. Semin Immunol. 16, 1-2, Kawai T. & Akira S. : Innate immune recognition of viral infection. Nat Immunol 7, 131-7, Kaisho T. & Akira S. : leiotropic function of Toll-like receptors. Microbes Infect 6, , Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, Terai K, Matsuda M, Inoue J, Uematsu S, Takeuchi O. & Akira S. : Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5, , Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, Matsuda M, Coban C, Ishii KJ, Kawai T, Takeuchi O. & Akira S. : Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR) 7- and TLR9-mediated interferon- {alpha} induction. J Exp Med 201, , Hoshino K, Sugiyama T, Matsumoto M, Tanaka T, Saito M, Hemmi H, Ohara O, Akira S. & Kaisho T. : IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9. Nature 440, , Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S. & Fujita T. : The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5, 730-7, 2004Ω. 11 Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O. & Akira S. : Cell Type-Specific Involvement of RIG-I in Antiviral Response. Immunity 23, 19-28, Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis ESC, Matsuura Y, Fujita T. & Akira S. : Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature, Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo YM, Gale M, Jr, Akira S, Yonehara S, Kato A. & Fujita T. : Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LG2 in antiviral innate immunity. J Immunol 175, , Rothenfusser S, Goutagny N, Dierna G, Gong M, Monks BG, Schoenemeyer A, Yamamoto M, Akira S. & Fitzgerald KA. : The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-i. J Immunol 175, , Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O. & Akira S. : IS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6, 981-8, Seth RB, Sun L, Ea CK. & Chen ZJ. : Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, , Xu LG, Wang YY, Han KJ, Li LY, Zhai Z. & Shu HB. : VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19, Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R. & Tschopp J. : Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, , Bowie A, Kiss-Toth E, Symons JA, Smith GL, Dower SK. & O'Neill LA. : A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling. roc Natl Acad Sci U S A 97, , Harte MT, Haga IR, Maloney G, Gray, Reading C, Bartlett NW, Smith GL, Bowie A. & O'Neill LA. : The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense. J Exp Med 197, , Stack J, Haga IR, Schroder M, Bartlett NW, Maloney G, Reading C, Fitzgerald KA, Smith GL. & Bowie AG. : Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. J Exp Med 201, , Foy E, Li K, Sumpter R Jr, Loo YM, Johnson CL, Wang C, Fish M, Yoneyama M, Fujita T, Lemon SM & Gale M Jr. : Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-i signaling. roc Natl Acad Sci U S A 102, , Li XD, Sun L, Seth RB, ineda G. & Chen ZJ. : Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. roc Natl Acad Sci U S A 102, , Andrejeva J, Childs KS, Young DF, Carlos TS, Stock N, Goodbourn S. & Randall RE. : The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. roc Natl Acad Sci U S A 101, , Kawane K, Fukuyama H, Yoshida H, Nagase H, Ohsawa Y, Uchiyama Y, Okada K, Iida T. & Nagata S. : Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation. Nat Immunol 4, , Yoshida H, Okabe Y, Kawane K, Fukuyama H. & Nagata S. : Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat Immunol 6, 49-56, Suzuki K, Mori A, Ishii KJ, Saito J, Singer DS, Klinman DM, Krause R. & Kohn LD. : Activation of target-tissue immune-recognition molecules by doublestranded polynucleotides. roc Natl Acad Sci U S A 96, , 1999.

8 8 56 pp 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, , 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, 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.