Antiviral signaling through pattern recognition receptors.

Viral infection is detected by the host innate immune system. Innate immune cells such as dendritic cells and macrophages detect nucleic acids derived from viruses through pattern recognition receptors (PRRs). Viral recognition by PRRs initiates the activation of signaling pathways that lead to production of type I interferon and inflammatory cytokines, which are important for the elimination of viruses. Two types of PRRs that recognize viral nucleic acids, Toll-like receptors (TLR) and RIG-I-like RNA helicases (RLH), have been identified. Of the TLRs, TLR3 recognizes viral double-stranded (ds) RNA, TLR7 and human TLR8 identify viral single-stranded (ss) RNA and TLR9 detects viral DNA. TLRs are located in endosomal compartments, whereas RLH are present in the cytoplasm where they detect viral dsRNA or ssRNA. Here we review the role of TLRs and RLHs in the antiviral innate immune response.

[1]  R. Medzhitov,et al.  Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA , 2006, Nature Immunology.

[2]  T. Maniatis,et al.  IKKε and TBK1 are essential components of the IRF3 signaling pathway , 2003, Nature Immunology.

[3]  Zhijian J. Chen,et al.  Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[4]  F. Martinon,et al.  RIP1 is an essential mediator of Toll-like receptor 3–induced NF-κB activation , 2004, Nature Immunology.

[5]  Shizuo Akira,et al.  Innate immune recognition of viral infection , 2006, Nature Immunology.

[6]  E. Nishida,et al.  Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF‐3 and CBP/p300 , 1998, The EMBO journal.

[7]  Hong-Hsing Liu,et al.  The specific and essential role of MAVS in antiviral innate immune responses. , 2006, Immunity.

[8]  Jiahuai Han,et al.  Identification of Lps2 as a key transducer of MyD88-independent TIR signalling , 2003, Nature.

[9]  C. Coban,et al.  A Toll-like receptor–independent antiviral response induced by double-stranded B-form DNA , 2006, Nature Immunology.

[10]  E. Fikrig,et al.  Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis , 2004, Nature Medicine.

[11]  E. Pietras,et al.  Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif , 2006, The EMBO journal.

[12]  K. Honda,et al.  Type I Inteferon Gene Induction by the Interferon Regulatory Factor Family of Transcription Factors , 2006 .

[13]  K. Honda,et al.  Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Hideo Negishi,et al.  IRF-7 is the master regulator of type-I interferon-dependent immune responses , 2005, Nature.

[15]  S. Akira,et al.  Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway , 2003, Science.

[16]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[17]  G. Barber,et al.  A FADD-dependent innate immune mechanism in mammalian cells , 2004, Nature.

[18]  S. Akira,et al.  IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9 , 2006, Nature.

[19]  Shizuo Akira,et al.  Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-β (TRIF) Associates with TNF Receptor-Associated Factor 6 and TANK-Binding Kinase 1, and Activates Two Distinct Transcription Factors, NF-κB and IFN-Regulatory Factor-3, in the Toll-Like Receptor Signaling 1 , 2003, The Journal of Immunology.

[20]  S. Akira,et al.  Small anti-viral compounds activate immune cells via the TLR7 MyD88–dependent signaling pathway , 2002, Nature Immunology.

[21]  Shizuo Akira,et al.  The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses , 2004, Nature Immunology.

[22]  S. Akira,et al.  Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. , 2004, Blood.

[23]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[24]  Qiang Sun,et al.  Dissociation of a MAVS/IPS-1/VISA/Cardif-IKKε Molecular Complex from the Mitochondrial Outer Membrane by Hepatitis C Virus NS3-4A Proteolytic Cleavage , 2006, Journal of Virology.

[25]  Hiroshi Takayanagi,et al.  Evidence for licensing of IFN-γ-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program , 2006, Proceedings of the National Academy of Sciences.

[26]  S. Akira,et al.  Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8 , 2004, Science.

[27]  J. Ferreon,et al.  Molecular Determinants of TRIF Proteolysis Mediated by the Hepatitis C Virus NS3/4A Protease* , 2005, Journal of Biological Chemistry.

[28]  Zhijian J. Chen Ubiquitin signalling in the NF-κB pathway , 2005, Nature Cell Biology.

[29]  R. Flavell,et al.  TLR-Independent Induction of Dendritic Cell Maturation and Adaptive Immunity by Negative-Strand RNA Viruses1 , 2004, The Journal of Immunology.

[30]  A. Pichlmair,et al.  RIG-I-Mediated Antiviral Responses to Single-Stranded RNA Bearing 5'-Phosphates , 2006, Science.

[31]  A. Shahangian,et al.  Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response , 2006, Nature.

[32]  Gunther Hartmann,et al.  5'-Triphosphate RNA Is the Ligand for RIG-I , 2006, Science.

[33]  Zhijian J. Chen,et al.  Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3 , 2005, Cell.

[34]  Tak W. Mak,et al.  Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors , 2005, Nature.

[35]  Richard A Flavell,et al.  Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[36]  R. Medzhitov,et al.  Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. , 2006, Immunity.

[37]  K. Ishii,et al.  Toll-Like Receptor 9 Signaling Activates NF-κB through IFN Regulatory Factor-8/IFN Consensus Sequence Binding Protein in Dendritic Cells1 , 2004, The Journal of Immunology.

[38]  S. Akira,et al.  The RNA Helicase Lgp2 Inhibits TLR-Independent Sensing of Viral Replication by Retinoic Acid-Inducible Gene-I1 , 2005, The Journal of Immunology.

[39]  K. Tyler,et al.  Does Toll-like receptor 3 play a biological role in virus infections? , 2004, Virology.

[40]  C. Coban,et al.  Essential role of IPS-1 in innate immune responses against RNA viruses , 2006, The Journal of experimental medicine.

[41]  William M. Lee,et al.  Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[42]  L. Glimcher,et al.  Osteopontin expression is essential for interferon-α production by plasmacytoid dendritic cells , 2006, Nature Immunology.

[43]  S. Akira,et al.  The Toll‐like receptor 7 (TLR7)‐specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily , 2003, European journal of immunology.

[44]  Guo-Ping Zhou,et al.  Triggering the Interferon Antiviral Response Through an IKK-Related Pathway , 2003, Science.

[45]  Shizuo Akira,et al.  Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA , 2004, Science.

[46]  Yong‐jun Liu,et al.  IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. , 2005, Annual review of immunology.

[47]  S. Akira,et al.  TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. , 2004, Immunity.

[48]  Shizuo Akira,et al.  Negative regulation of interferon-regulatory factor 3–dependent innate antiviral response by the prolyl isomerase Pin1 , 2006, Nature Immunology.

[49]  Katherine A. Fitzgerald,et al.  Rip1 Mediates the Trif-dependent Toll-like Receptor 3- and 4-induced NF-κB Activation but Does Not Contribute to Interferon Regulatory Factor 3 Activation* , 2005, Journal of Biological Chemistry.

[50]  Osamu Takeuchi,et al.  The Roles of Two IκB Kinase-related Kinases in Lipopolysaccharide and Double Stranded RNA Signaling and Viral Infection , 2004, The Journal of experimental medicine.

[51]  Akiko Iwasaki,et al.  Recognition of single-stranded RNA viruses by Toll-like receptor 7. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M. Mann,et al.  Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6 , 2006, Nature.

[53]  S. Akira,et al.  Toll-like receptor function and signaling. , 2006, The Journal of allergy and clinical immunology.

[54]  Z. Zhai,et al.  VISA Is an Adapter Protein Required for Virus-Triggered IFN-β Signaling , 2005 .

[55]  Shizuo Akira,et al.  Shared and Unique Functions of the DExD/H-Box Helicases RIG-I, MDA5, and LGP2 in Antiviral Innate Immunity1 , 2005, The Journal of Immunology.

[56]  C. Coban,et al.  Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6 , 2004, Nature Immunology.

[57]  K. Honda,et al.  Negative regulation of Toll-like-receptor signaling by IRF-4. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[58]  S. Akira,et al.  A Toll-like receptor recognizes bacterial DNA , 2000, Nature.

[59]  S. Akira,et al.  Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7 , 2005, Nature Medicine.

[60]  Stanley M Lemon,et al.  Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[61]  R. Flavell,et al.  Toll-like receptor 3 promotes cross-priming to virus-infected cells , 2005, Nature.

[62]  G. Trinchieri,et al.  Plasmacytoid dendritic cells in immunity , 2004, Nature Immunology.

[63]  Ralf Bartenschlager,et al.  Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus , 2005, Nature.