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Innate immune recognition of viral infection

Abstract

Induction of the antiviral innate immune response depends on recognition of viral components by host pattern-recognition receptors. Members of the Toll-like receptor family have emerged as key sensors that recognize viral components such as nucleic acids. Toll-like receptor signaling results in the production of type I interferon and inflammatory cytokines and leads to dendritic cell maturation and establishment of antiviral immunity. Cells also express cytoplasmic RNA helicases that function as alternative pattern-recognition receptors through recognition of double-stranded RNA produced during virus replication. These two classes of pattern-recognition receptor molecules are expressed in different intracellular compartments and induce type I interferon responses via distinct signaling pathways.

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References

  1. 1

    Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5, 987–995 (2004).

  2. 2

    Theofilopoulos, A.N., Baccala, R., Beutler, B. & Kono, D.H. Type I interferons (α/β) in immunity and autoimmunity. Annu. Rev. Immunol. 23, 307–336 (2005).

  3. 3

    Takeda, K. & Akira, S. Toll-like receptors in innate immunity. Int. Immunol. 17, 1–14 (2005).

  4. 4

    Medzhitov, R. & Janeway, C.A., Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell 91, 295–298 (1997).

  5. 5

    Janeway, C.A., Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

  6. 6

    Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2, 675–680 (2001).

  7. 7

    Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

  8. 8

    Le Bon, A. & Tough, D.F. Links between innate and adaptive immunity via type I interferon. Curr. Opin. Immunol. 14, 432–436 (2002).

  9. 9

    Takaoka, A. & Taniguchi, T. New aspects of IFN-α/β signalling in immunity, oncogenesis and bone metabolism. Cancer Sci. 94, 405–411 (2003).

  10. 10

    Bonizzi, G. & Karin, M. The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280–288 (2004).

  11. 11

    Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3, 196–200 (2002).

  12. 12

    Diebold, S.S. et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).

  13. 13

    Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).

  14. 14

    Lund, J.M. et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl. Acad. Sci. USA 101, 5598–5603 (2004).

  15. 15

    Krug, A. et al. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 21, 107–119 (2004).

  16. 16

    Lund, J., Sato, A., Akira, S., Medzhitov, R. & Iwasaki, A. Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J. Exp. Med. 198, 513–520 (2003).

  17. 17

    Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004).

  18. 18

    Kato, H. et al. Cell type specific involvment of RIG-I in antiviral response. Immunity 23, 19–28 (2005).

  19. 19

    Liu, Y.J. IPC: Professional type I interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275–306 (2005).

  20. 20

    Colonna, M., Trinchieri, G. & Liu, Y.J. Plasmacytoid dendritic cells in immunity. Nat. Immunol. 5, 1219–1226 (2004).

  21. 21

    Hornung, V. et al. Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat. Med. 11, 263–270 (2005).

  22. 22

    Jurk, M. et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat. Immunol. 3, 499 (2002).

  23. 23

    Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).

  24. 24

    Hemmi, H., Kaisho, T., Takeda, K. & Akira, S. The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J. Immunol. 170, 3059–3064 (2003).

  25. 25

    Krug, A. et al. Herpes simplex virus type 1 activates murine natural interferon-producing cells through Toll-like receptor 9. Blood 103, 1433–1437 (2004).

  26. 26

    Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. 5, 190–198 (2004).

  27. 27

    Akira, S. & Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511 (2004).

  28. 28

    Deng, L. et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103, 351–361 (2000).

  29. 29

    Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001).

  30. 30

    Ishitani, T. et al. Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling. EMBO J. 22, 6277–6288 (2003).

  31. 31

    Jin, G. et al. Identification of a human NF-κB-activating protein, TAB3. Proc. Natl. Acad. Sci. USA 101, 2028–2033 (2004).

  32. 32

    Sato, S. et al. Essential role of TAK1 in innate and adaptive immune responses. Nat. Immunol. 6, 1087–1095 (2005).

  33. 33

    Kawai, T., Adachi, O., Ogawa, T., Takeda, K. & Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115–122 (1999).

  34. 34

    Kawai, T. et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J. Immunol. 167, 5887–5894 (2001).

  35. 35

    Kaisho, T., Takeuchi, O., Kawai, T., Hoshino, K. & Akira, S. Endotoxin-induced maturation of MyD88-deficient dendritic cells. J. Immunol. 166, 5688–5694 (2001).

  36. 36

    Hoshino, K., Kaisho, T., Iwabe, T., Takeuchi, O. & Akira, S. Differential involvement of IFN-β in Toll-like receptor-stimulated dendritic cell activation. Int. Immunol. 14, 1225–1231 (2002).

  37. 37

    Kawai, T. et al. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5, 1061–1068 (2004).

  38. 38

    Honda, K. et al. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc. Natl. Acad. Sci. USA 101, 15416–15421 (2004).

  39. 39

    Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005).

  40. 40

    Coccia, E.M. et al. Viral infection and Toll-like receptor agonists induce a differential expression of type I and λ-interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur. J. Immunol. 34, 796–805 (2004).

  41. 41

    Dai, J., Megjugorac, N.J., Amrute, S.B. & Fitzgerald-Bocarsly, P. Regulation of IFN regulatory factor-7 and IFN-α production by enveloped virus and lipopolysaccharide in human plasmacytoid dendritic cells. J. Immunol. 173, 1535–1548 (2004).

  42. 42

    Uematsu, S. et al. Interleukin-1 receptor-associated kinase-1 (IRAK-1) plays an essential role for TLR7- and TLR9-mediated interferon-α induction. J. Exp. Med. 201, 915–923 (2005).

  43. 43

    Honda, K. et al. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035–1040 (2005).

  44. 44

    Takaoka, A. et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434, 243–249 (2005).

  45. 45

    Schoenemeyer, A. et al. The interferon regulatory factor, IRF5, is a central mediator of TLR7 signaling. J. Biol. Chem. 280, 17005–17012 (2005).

  46. 46

    Alexopoulou, L., Holt, A.C., Medzhitov, R. & Flavell, R.A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001).

  47. 47

    Tabeta, K. et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc. Natl. Acad. Sci. USA 101, 3516–3521 (2004).

  48. 48

    Wang, T. et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat. Med. 10, 1366–1373 (2004).

  49. 49

    Schulz, O. et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433, 887–892 (2005).

  50. 50

    Matsumoto, M. et al. Subcellular localization of Toll-like receptor 3 in human dendritic cells. J. Immunol. 171, 3154–3162 (2003).

  51. 51

    Yamamoto, M. et al. A novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling. J. Immunol. 169, 6668–6672 (2002).

  52. 52

    Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T. & Seya, T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nat. Immunol. 4, 161–167 (2003).

  53. 53

    Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301, 640–643 (2003).

  54. 54

    Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743–748 (2003).

  55. 55

    Sharma, S. et al. Triggering the interferon antiviral response through an IKK-related pathway. Science 300, 1148–1151 (2003).

  56. 56

    Fitzgerald, K.A. et al. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4, 491–496 (2003).

  57. 57

    McWhirter, S.M. et al. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc. Natl. Acad. Sci. USA 101, 233–238 (2004).

  58. 58

    Hemmi, H. et al. The roles of two IκB kinase-related kinases in lipopolysaccharide and double-stranded RNA signaling and viral infection. J. Exp. Med. 199, 1641–1650 (2004).

  59. 59

    Perry, A.K., Chow, E.K., Goodnough, J.B., Yeh, W.C. & Cheng, G. Differential requirement for TANK-binding kinase-1 in type I interferon responses to Toll-like receptor activation and viral infection. J. Exp. Med. 199, 1651–1658 (2004).

  60. 60

    Sato, S. 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. J. Immunol. 171, 4304–4310 (2003).

  61. 61

    Meylan, E. et al. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-κB activation. Nat. Immunol. 5, 503–507 (2004).

  62. 62

    Gohda, J., Matsumura, T. & Inoue, J. TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF)-dependent pathway in TLR signaling. J. Immunol. 173, 2913–2917 (2004).

  63. 63

    Edelmann, K.H. et al. Does Toll-like receptor 3 play a biological role in virus infections? Virology 322, 231–238 (2004).

  64. 64

    Lopez, C.B. et al. TLR-independent induction of dendritic cell maturation and adaptive immunity by negative-strand RNA viruses. J. Immunol. 173, 6882–6889 (2004).

  65. 65

    Hornung, V. et al. Replication-dependent potent IFN-α induction in human plasmacytoid dendritic cells by a single-stranded RNA virus. J. Immunol. 173, 5935–5943 (2004).

  66. 66

    Kang, D.C. et al. mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proc. Natl. Acad. Sci. USA 99, 637–642 (2002).

  67. 67

    Kovacsovics, M. et al. Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation. Curr. Biol. 12, 838–843 (2002).

  68. 68

    Andrejeva, J. et al. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, Mda-5, and inhibit its activation of the IFN-β promoter. Proc. Natl Acad. Sci. USA 101, 17264–17269 (2004).

  69. 69

    Yoneyama, M. et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol. 175, 2851–2858 (2005).

  70. 70

    Rothenfusser, S. et al. The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J. Immunol. 175, 5260–5268 (2005).

  71. 71

    Balachandran, S., Thomas, E. & Barber, G.N. A FADD-dependent innate immune mechanism in mammalian cells. Nature 432, 401–405 (2004).

  72. 72

    Hoffmann, J.A. The immune response of Drosophila. Nature 426, 33–38 (2003).

  73. 73

    Kawai, T. et al. IPS-1; an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6, 981–988 (2005).

  74. 74

    Seth, R.B., Sun, L., Ea, C.K. & Chen, Z.J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF3. Cell 122, 669–682 (2005).

  75. 75

    Xu, L.G. et al. VISA is an adapter protein required for virus-triggered IFN-β signaling. Mol. Cell 19, 727–740 (2005).

  76. 76

    Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005).

  77. 77

    Sen, G.C. & Sarkar, S.N. Hitching RIG to action. Nat. Immunol. 6, 1074–1076 (2005).

  78. 78

    Stack, J. et al. Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. J. Exp. Med. 201, 1007–1018 (2005).

  79. 79

    Foy, E. et al. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc. Natl. Acad. Sci. USA 102, 2986–2991 (2005).

  80. 80

    Sumpter, R., Jr. et al. Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J. Virol. 79, 2689–2699 (2005).

  81. 81

    Li, K. et al. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc. Natl. Acad. Sci. USA 102, 2992–2997 (2005).

  82. 82

    Ferreon, J.C., Ferreon, A.C., Li, K. & Lemon, S.M. Molecular determinants of TRIF proteolysis mediated by the hepatitis C virus NS3/4A protease. J. Biol. Chem. 280, 20483–20492 (2005).

  83. 83

    Yu, Y., Wang, S.E. & Hayward, G.S. The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity 22, 59–70 (2005).

  84. 84

    Boule, M.W. et al. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin–immunoglobulin G complexes. J. Exp. Med. 199, 1631–1640 (2004).

  85. 85

    Means, T.K. et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115, 407–417 (2005).

  86. 86

    Yoshida, H., Okabe, Y., Kawane, K., Fukuyama, H. & Nagata, S. Lethal anemia caused by interferon-β produced in mouse embryos carrying undigested DNA. Nat. Immunol. 6, 49–56 (2005).

  87. 87

    Ishii, K.J. et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. (in the press).

  88. 88

    Kim, T. et al. Activation of interferon regulatory factor 3 in response to DNA-damaging agents. J. Biol. Chem. 274, 30686–30689 (1999).

  89. 89

    Hur, G.M. et al. The death domain kinase RIP has an essential role in DNA damage-induced NF-κB activation. Genes Dev. 17, 873–882 (2003).

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Acknowledgements

We thank all members of our laboratory for discussions and insights.

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Correspondence to Shizuo Akira.

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Figure 1: Recognition of viral nucleic acids by TLR7, TLR8 and TLR9 in pDCs.
Figure 2: TLR3-dependent signaling pathway.
Figure 3: Signaling pathway triggered by RIG-I, Mda5 and DNA.