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  • Review Article
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Recognition of herpesviruses by the innate immune system

Nature Reviews Immunology volume 11, pages 143–154 (2011)Cite this article

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An Erratum to this article was published on 28 June 2013

This article has been updated

Key Points

  • Herpesviruses are a large family of DNA viruses, eight of which can cause diseases in humans, particularly in children and immunocompromised individuals. All herpesviruses have the capacity to cause lytic infection in permissive cells and to establish latent or recurrent infections in other cell types.

  • The innate immune system detects infections using germline-encoded pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are membrane-bound PRRs that detect microorganisms in extracellular and endosomal locations. TLR2, TLR3 and TLR9 are well-described sensors of herpesvirus infections.

  • In the cytoplasm, active innate immune surveillance takes place and is mediated by nucleic acid sensors. Herpesvirus infections are sensed by both RNA and DNA sensing systems, and recent reports suggest a particularly important role for the cytosolic DNA-sensing AIM2-like receptor (ALR) family in intracellular detection of herpesviruses.

  • Given the relatively slow replication cycle of herpesviruses and the establishment of life-long infections, these viruses are highly dependent on efficient immune evasion strategies. It is now known that herpesviruses evade all classes of PRRs (including ALRs), as well as the downstream signalling machinery.

  • Innate immune defence against herpesviruses is highly dependent on the type I interferon system and natural killer cells. Model studies in mice and genetic data from humans have revealed essential roles for both TLRs and intracellular DNA sensors in mounting protective immune responses against herpesviruses.

Abstract

Advances in innate immunity over the past decade have revealed distinct classes of pattern recognition receptors (PRRs) that detect pathogens at the cell surface and in intracellular compartments. This has shed light on how herpesviruses, which are large disease-causing DNA viruses that replicate in the nucleus, are initially recognized during cellular infection. Surprisingly, this involves multiple PRRs both on the cell surface and within endosomes and the cytosol. In this article we describe recent advances in our understanding of innate detection of herpesviruses, how this innate detection translates into anti-herpesvirus host defence, and how the viruses seek to evade this innate detection to establish persistent infections.

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Figure 1: Innate immune recognition and activation by herpesviruses.
Figure 2: Intracellular detection of herpesvirus DNA and activation of signal transduction.
Figure 3: Herpesvirus evasion of PRR-mediated recognition, signalling and gene expression.

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Change history

  • 28 June 2013

    In Figure 3 of the original version of this article, viral RNA was shown to interact with TLR9 and viral DNA was shown to interact with TLR3. This is incorrect and instead viral RNA interacts with TLR3 and viral DNA interacts with TLR9. This has now been corrected online. Nature Reviews Immunology apologizes for this error.

References

  1. Pellett, P. E. & Roizman, B. The Family: Herpesviridae A Brief Introduction in Fields Virology 2479–2500 (Lippincort, Williams & Wilkins, Philadelphia, 2007).

    Google Scholar 

  2. Liu, T., Khanna, K. M., Chen, X., Fink, D. J. & Hendricks, R. L. CD8+ T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons. J. Exp. Med. 191, 1459–1466 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Liu, T., Khanna, K. M., Carriere, B. N. & Hendricks, R. L. Gamma interferon can prevent herpes simplex virus type 1 reactivation from latency in sensory neurons. J. Virol. 75, 11178–11184 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Reusser, P., Riddell, S. R., Meyers, J. D. & Greenberg, P. D. Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 78, 1373–1380 (1991).

    CAS  PubMed  Google Scholar 

  5. Braaten, D. C., Sparks-Thissen, R. L., Kreher, S., Speck, S. H. & Virgin, H. W. An optimized CD8+ T-cell response controls productive and latent gammaherpesvirus infection. J. Virol. 79, 2573–2583 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dupuis, S. et al. Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency. Nature Genet. 33, 388–391 (2003). This paper showed that patients with STAT1 deficiency do not respond to type I IFNs and are susceptible to herpes simplex virus encephalitis.

    Article  CAS  PubMed  Google Scholar 

  7. Salazar-Mather, T. P., Lewis, C. A. & Biron, C. A. Type I interferons regulate inflammatory cell trafficking and macrophage inflammatory protein 1α delivery to the liver. J. Clin. Invest. 110, 321–330 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Biron, C. A., Byron, K. S. & Sullivan, J. L. Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320, 1731–1735 (1989).

    Article  CAS  PubMed  Google Scholar 

  9. Rager-Zisman, B., Quan, P. C., Rosner, M., Moller, J. R. & Bloom, B. R. Role of NK cells in protection of mice against herpes simplex virus-1 infection. J. Immunol. 138, 884–888 (1987).

    CAS  PubMed  Google Scholar 

  10. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Schlee, M. et al. Recognition of 5′ triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity 31, 25–34 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schmidt, A. et al. 5′-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I. Proc. Natl Acad. Sci. USA 106, 12067–12072 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pichlmair, A. et al. Activation of MDA5 requires higher-order RNA structures generated during virus infection. J. Virol. 83, 10761–10769 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Takaoka, A. et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501–505 (2007). DAI was the first cytoplasmic DNA sensor to be identified, and was shown to contribute to the type I IFN response to HSV-1 infection.

    Article  CAS  PubMed  Google Scholar 

  15. Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514–518 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Burckstummer, T. et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nature Immunol. 10, 266–272 (2009).

    Article  CAS  Google Scholar 

  17. Fernandes-Alnemri, T., Yu, J. W., Datta, P., Wu, J. & Alnemri, E. S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509–513 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Roberts, T. L. et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323, 1057–1060 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Ablasser, A. et al. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nature Immunol. 10, 1065–1072 (2009).

    Article  CAS  Google Scholar 

  20. Chiu, Y. H., Macmillan, J. B. & Chen, Z. J. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138, 576–591 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang, P. et al. The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a β-catenin-dependent pathway. Nature Immunol. 11, 487–494 (2010).

    Article  CAS  Google Scholar 

  22. Unterholzner, L. et al. IFI16 is an innate immune sensor for intracellular DNA. Nature Immunol. 11, 997–1004 (2010). This paper identifies IFI16 as an intracellular sensor of DNA, and shows that it is essential for the IFN and cytokine response to HSV-1 infection. The work is also the first to demonstrate the presence free viral genomic DNA in the cytoplasm during infection.

    Article  CAS  Google Scholar 

  23. Poeck, H. et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1β production. Nature Immunol. 11, 63–69 (2010).

    Article  CAS  Google Scholar 

  24. Mogensen, T. H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 22, 240–273 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Honda, K. & Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nature Rev. Immunol. 6, 644–658 (2006).

    Article  CAS  Google Scholar 

  26. Gugliesi, F. et al. The proapoptotic activity of the interferon-inducible gene IFI16 provides new insights into its etiopathogenetic role in autoimmunity. J. Autoimmun. 35, 114–123 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Chandran, B. Early events in Kaposi's sarcoma-associated herpesvirus infection of target cells. J. Virol. 84, 2188–2199 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Melroe, G. T., DeLuca, N. A. & Knipe, D. M. Herpes simplex virus 1 has multiple mechanisms for blocking virus-induced interferon production. J. Virol. 78, 8411–8420 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cristea, I. M. et al. Human cytomegalovirus pUL83 stimulates activity of the viral immediate-early promoter through its interaction with the cellular IFI16 protein. J. Virol. 84, 7803–7814 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cotter, C. R. et al. The virion host shut-off (vhs) protein blocks a TLR-independent pathway of herpes simplex virus type 1 recognition in human and mouse dendritic cells. PLoS ONE 5, e8684 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Rebsamen, M. et al. DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-κB. EMBO Rep. 10, 916–922 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wu, L. et al. Epstein-Barr virus LF2: an antagonist to type I interferon. J. Virol. 83, 1140–1146 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. van Lint, A. L. et al. Herpes simplex virus immediate-early ICP0 protein inhibits TLR2-dependent inflammatory responses and NF-κB signaling. J. Virol. 84, 10802–10811 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Orvedahl, A. et al. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1, 23–35 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Melchjorsen, J., Siren, J., Julkunen, I., Paludan, S. R. & Matikainen, S. Induction of cytokine expression by herpes simplex virus in human monocyte-derived macrophages and dendritic cells is dependent on virus replication and is counteracted by ICP27 targeting NF-κB and IRF-3. J. Gen.Virol. 87, 1099–1108 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Verpooten, D., Ma, Y., Hou, S., Yan, Z. & He, B. Control of TANK-binding kinase 1-mediated signaling by the γ134.5 protein of herpes simplex virus 1. J. Biol. Chem. 284, 1097–1105 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jong, J. E., Park, J., Kim, S. & Seo, T. Kaposi's sarcoma-associated herpesvirus viral protein kinase interacts with RNA helicase A and regulates host gene expression. J. Microbiol. 48, 206–212 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Zhu, F. X., King, S. M., Smith, E. J., Levy, D. E. & Yuan, Y. A Kaposi's sarcoma-associated herpesviral protein inhibits virus-mediated induction of type I interferon by blocking IRF-7 phosphorylation and nuclear accumulation. Proc. Natl Acad. Sci. USA 99, 5573–5578 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jaworska, J., Gravel, A., Fink, K., Grandvaux, N. & Flamand, L. Inhibition of transcription of the β interferon gene by the human herpesvirus 6 immediate-early 1 protein. J. Virol. 81, 5737–5748 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lubyova, B. & Pitha, P. M. Characterization of a novel human herpesvirus 8-encoded protein, vIRF-3, that shows homology to viral and cellular interferon regulatory factors. J. Virol. 74, 8194–8201 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Taylor, R. T. & Bresnahan, W. A. Human cytomegalovirus IE86 attenuates virus- and tumor necrosis factor α-induced NFκB-dependent gene expression. J. Virol. 80, 10763–10771 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cloutier, N. & Flamand, L. Kaposi sarcoma-associated herpesvirus latency-associated nuclear antigen inhibits interferon (IFN) β expression by competing with IFN regulatory factor-3 for binding to IFNB promoter. J. Biol. Chem. 285, 7208–7221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sen, N. et al. Varicella zoster virus immediate early protein 62 blocks IRF3 phosphorylation at key serine residues: a novel mechanism of IRF3 inhibition among herpesviruses. J. Virol. 84, 9240–9253 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Akhtar, J. & Shukla, D. Viral entry mechanisms: cellular and viral mediators of herpes simplex virus entry. FEBS J. 276, 7228–7236 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Subramanian, R. P. & Geraghty, R. J. Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B. Proc. Natl Acad. Sci. USA 104, 2903–2908 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Atanasiu, D., Saw, W. T., Cohen, G. H. & Eisenberg, R. J. Cascade of events governing cell-cell fusion induced by herpes simplex virus glycoproteins gD, gH/gL, and gB. J. Virol. 84, 12292–12299 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Boehme, K. W., Guerrero, M. & Compton, T. Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells. J. Immunol. 177, 7094–7102 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Compton, T. et al. Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J. Virol. 77, 4588–4596 (2003). This paper was the first to identify a TLR involved in the recognition of a herpesvirus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kurt-Jones, E. A. et al. Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. Proc. Natl Acad. Sci. USA 101, 1315–1320 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sorensen, L. N. et al. TLR2 and TLR9 synergistically control herpes simplex virus infection in the brain. J. Immunol. 181, 8604–8612 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Wang, J. P. et al. Varicella-zoster virus activates inflammatory cytokines in human monocytes and macrophages via Toll-like receptor 2. J. Virol. 79, 12658–12666 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gaudreault, E., Fiola, S., Olivier, M. & Gosselin, J. Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. J. Virol. 81, 8016–8024 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sato, A., Linehan, M. M. & Iwasaki, A. Dual recognition of herpes simplex viruses by TLR2 and TLR9 in dendritic cells. Proc. Natl Acad. Sci. USA 103, 17343–17348 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Reske, A., Pollara, G., Krummenacher, C., Katz, D. R. & Chain, B. M. Glycoprotein-dependent and TLR2-independent innate immune recognition of herpes simplex virus-1 by dendritic cells. J. Immunol. 180, 7525–7536 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Barbalat, R., Lau, L., Locksley, R. M. & Barton, G. M. Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands. Nature Immunol. 10, 1200–1207 (2009).

    Article  CAS  Google Scholar 

  56. Szomolanyi-Tsuda, E., Liang, X., Welsh, R. M., Kurt-Jones, E. A. & Finberg, R. W. Role for TLR2 in NK cell-mediated control of murine cytomegalovirus in vivo. J. Virol. 80, 4286–4291 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bochud, P. Y., Magaret, A. S., Koelle, D. M., Aderem, A. & Wald, A. Polymorphisms in TLR2 are associated with increased viral shedding and lesional rate in patients with genital herpes simplex virus type 2 infection. J. Infect. Dis. 196, 505–509 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Kijpittayarit, S., Eid, A. J., Brown, R. A., Paya, C. V. & Razonable, R. R. Relationship between Toll-like receptor 2 polymorphism and cytomegalovirus disease after liver transplantation. Clin. Infect. Dis. 44, 1315–1320 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Ahmad-Nejad, P. et al. Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur. J. Immunol. 32, 1958–1968 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. 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). This paper was the first to identify a TLR involved in the recognition of herpesvirus nucleic acids.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    Article  CAS  PubMed  Google Scholar 

  62. Varani, S. et al. Human cytomegalovirus differentially controls B cell and T cell responses through effects on plasmacytoid dendritic cells. J. Immunol. 179, 7767–7776 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Lim, W. H., Kireta, S., Russ, G. R. & Coates, P. T. Human plasmacytoid dendritic cells regulate immune responses to Epstein-Barr virus (EBV) infection and delay EBV-related mortality in humanized NOD-SCID mice. Blood 109, 1043–1050 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Fiola, S., Gosselin, D., Takada, K. & Gosselin, J. TLR9 contributes to the recognition of EBV by primary monocytes and plasmacytoid dendritic cells. J. Immunol. 185, 3620–3631 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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).

    Article  CAS  PubMed  Google Scholar 

  67. Guggemoos, S. et al. TLR9 contributes to antiviral immunity during gammaherpesvirus infection. J. Immunol. 180, 438–443 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Yasuda, K. et al. Requirement for DNA CpG content in TLR9-dependent dendritic cell activation induced by DNA-containing immune complexes. J. Immunol. 183, 3109–3117 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Haas, T. et al. The DNA sugar backbone 2′ deoxyribose determines Toll-like receptor 9 activation. Immunity 28, 315–323 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  71. Delale, T. et al. MyD88-dependent and -independent murine cytomegalovirus sensing for IFN-α release and initiation of immune responses in vivo. J. Immunol. 175, 6723–6732 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Rasmussen, S. B. et al. Type I IFN production during HSV infection is controlled by cell-type specific viral recognition by TLR9, the mitochondrial antiviral signaling protein pathway, and novel recognition systems. J. Virol. 81, 13315–13324 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sarangi, P. P., Kim, B., Kurt-Jones, E. & Rouse, B. T. Innate recognition network driving herpes simplex virus-induced corneal immunopathology: role of the toll pathway in early inflammatory events in stromal keratitis. J. Virol. 81, 11128–11138 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lund, J. M., Linehan, M. M., Iijima, N. & Iwasaki, A. Cutting edge: plasmacytoid dendritic cells provide innate immune protection against mucosal viral infection in situ. J. Immunol. 177, 7510–7514 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Wuest, T. et al. Intact TRL 9 and type I interferon signaling pathways are required to augment HSV-1 induced corneal CXCL9 and CXCL10. J. Neuroimmunol. 179, 46–52 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zucchini, N. et al. Cutting edge: overlapping functions of TLR7 and TLR9 for innate defense against a herpesvirus infection. J. Immunol. 180, 5799–5803 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Hokeness-Antonelli, K. L., Crane, M. J., Dragoi, A. M., Chu, W. M. & Salazar-Mather, T. P. IFN-αβ-mediated inflammatory responses and antiviral defense in liver is TLR9-independent but MyD88-dependent during murine cytomegalovirus infection. J. Immunol. 179, 6176–6183 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Ku, C. L. et al. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J. Exp. Med. 204, 2407–2422 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Weber, F., Wagner, V., Rasmussen, S. B., Hartmann, R. & Paludan, S. R. Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses. J. Virol. 80, 5059–5064 (2006). This report showed that double-stranded RNA accumulates in the cytoplasm of permissive cells infected with HSV-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 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).

    Article  CAS  PubMed  Google Scholar 

  81. Iwakiri, D. et al. Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from Toll-like receptor 3. J. Exp. Med. 206, 2091–2099 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Miettinen, M., Sareneva, T., Julkunen, I. & Matikainen, S. IFNs activate Toll-like receptor gene expression in viral infections. Genes Immun. 2, 349–355 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  85. Davey, G. M. et al. Cutting edge: priming of CD8 T cell immunity to herpes simplex virus type 1 requires cognate TLR3 expression in vivo. J. Immunol. 184, 2243–2246 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Zhang, S. Y. et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science 317, 1522–1527 (2007). This study showed that patients with TLR3 deficiency exhibit an impaired IFN response to HSV-1 infection in vitro and enhanced susceptibility to herpes simplex virus encephalitis.

  87. Ranjith-Kumar, C. T. et al. Effects of single nucleotide polymorphisms on Toll-like receptor 3 activity and expression in cultured cells. J. Biol. Chem. 282, 17696–17705 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Willmann, O., Ahmad-Nejad, P., Neumaier, M., Hennerici, M. G. & Fatar, M. Toll-like receptor 3 immune deficiency may be causative for HSV-2-associated mollaret meningitis. Eur. Neurol. 63, 249–251 (2010).

    Article  PubMed  Google Scholar 

  89. Sciortino, M. T., Suzuki, M., Taddeo, B. & Roizman, B. RNAs extracted from herpes simplex virus 1 virions: apparent selectivity of viral but not cellular RNAs packaged in virions. J. Virol. 75, 8105–8116 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bresnahan, W. A. & Shenk, T. A subset of viral transcripts packaged within human cytomegalovirus particles. Science 288, 2373–2376 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Malmgaard, L., Melchjorsen, J., Bowie, A. G., Mogensen, S. C. & Paludan, S. R. Viral activation of macrophages through TLR-dependent and -independent pathways. J. Immunol. 173, 6890–6898 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Samanta, M., Iwakiri, D., Kanda, T., Imaizumi, T. & Takada, K. EB virus-encoded RNAs are recognized by RIG-I and activate signaling to induce type I IFN. EMBO J. 25, 4207–4214 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Samanta, M., Iwakiri, D. & Takada, K. Epstein-Barr virus-encoded small RNA induces IL-10 through RIG-I-mediated IRF-3 signaling. Oncogene 27, 4150–4160 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Melchjorsen, J. et al. Early innate recognition of herpes simplex virus in human primary macrophages is mediated via the MDA5/MAVS-dependent and MDA5/MAVS/RNA polymerase III-independent pathways. J. Virol. 84, 11350–11358 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  96. Ishii, K. J. et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nature Immunol. 7, 40–48 (2006). This paper was the first to report that herpesvirus (HSV and HCMV) DNA has the capacity to stimulate innate immune responses through cytosolic PRRs.

    Article  CAS  Google Scholar 

  97. Ishii, K. J. et al. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature 451, 725–729 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Defilippis, V. R. et al. Activation of the interferon response by human cytomegalovirus occurs via cytoplasmic double-stranded DNA but not glycoprotein B. J. Virol. 84, 8913–8925 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. DeFilippis, V. R., Alvarado, D., Sali, T., Rothenburg, S. & Fruh, K. Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1. J. Virol. 84, 585–598 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Cheng, G., Zhong, J., Chung, J. & Chisari, F. V. Double-stranded DNA and double-stranded RNA induce a common antiviral signaling pathway in human cells. Proc. Natl Acad. Sci. USA 104, 9035–9040 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Choi, M. K. et al. A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA. Proc. Natl Acad. Sci. USA 106, 17870–17875 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kim, T. et al. Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells. Proc. Natl Acad. Sci. USA 107, 15181–15186 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Yan, H. et al. RPA nucleic acid-binding properties of IFI16-HIN200. Biochim. Biophys. Acta 1784, 1087–1097 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Mondini, M. et al. The interferon-inducible HIN-200 gene family in apoptosis and inflammation: implication for autoimmunity. Autoimmunity 43, 226–231 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Rathinam, V. A. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nature Immunol. 11, 395–402 (2010). This work is the first to demonstrate an essential role for a cytoplasmic DNA sensor in the innate immune response to a herpesvirus (MCMV).

    Article  CAS  Google Scholar 

  106. Hertel, L. et al. The interferon-inducible 204 gene, a member of the Ifi 200 family, is not involved in the antiviral state induction by IFN-α, but is required by the mouse cytomegalovirus for its replication. Virology 262, 1–8 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Rehwinkel, J. et al. RIG-I detects viral genomic RNA during negative-strand RNA virus infection. Cell 140, 397–408 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Lee, H. K., Lund, J. M., Ramanathan, B., Mizushima, N. & Iwasaki, A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315, 1398–1401 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Melchjorsen, J. & Paludan, S. R. Induction of RANTES/CCL5 by herpes simplex virus is regulated by nuclear factor κB and interferon regulatory factor 3. J. Gen. Virol. 84, 2491–2495 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Delboy, M. G., Roller, D. G. & Nicola, A. V. Cellular proteasome activity facilitates herpes simplex virus entry at a postpenetration step. J. Virol. 82, 3381–3390 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Soulat, D. et al. The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. EMBO J. 27, 2135–2146 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Schroder, M., Baran, M. & Bowie, A. G. Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKɛ-mediated IRF activation. EMBO J. 27, 2147–2157 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009). References 113 and 114 identify and describe STING as an essential adaptor in intracellular DNA signalling, and reveal the importance of subcellular localization in innate immune recognition and signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Saitoh, T. et al. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc. Natl Acad. Sci. USA 106, 20842–20846 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Smiley, J. R. Herpes simplex virus virion host shutoff protein: immune evasion mediated by a viral RNase? J. Virol. 78, 1063–1068 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kawai, T. & Akira, S. Innate immune recognition of viral infection. Nature Immunol. 7, 131–137 (2006).

    Article  CAS  Google Scholar 

  118. Abate, D. A., Watanabe, S. & Mocarski, E. S. Major human cytomegalovirus structural protein pp65 (ppUL83) prevents interferon response factor 3 activation in the interferon response. J. Virol. 78, 10995–11006 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Browne, E. P. & Shenk, T. Human cytomegalovirus UL83-coded pp65 virion protein inhibits antiviral gene expression in infected cells. Proc. Natl Acad. Sci. USA 100, 11439–11444 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. McGregor, A., Liu, F. & Schleiss, M. R. Molecular, biological, and in vivo characterization of the guinea pig cytomegalovirus (CMV) homologs of the human CMV matrix proteins pp71 (UL82) and pp65 (UL83). J. Virol. 78, 9872–9889 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Leib, D. A. et al. Interferons regulate the phenotype of wild-type and mutant herpes simplex viruses in vivo. J. Exp. Med. 189, 663–672 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Saira, K., Zhou, Y. & Jones, C. The infected cell protein 0 encoded by bovine herpesvirus 1 (bICP0) induces degradation of interferon response factor 3 and, consequently, inhibits β interferon promoter activity. J. Virol. 81, 3077–3086 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Paladino, P., Collins, S. E. & Mossman, K. L. Cellular localization of the herpes simplex virus ICP0 protein dictates its ability to block IRF3-mediated innate immune responses. PLoS ONE 5, e10428 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Melroe, G. T., Silva, L., Schaffer, P. A. & Knipe, D. M. Recruitment of activated IRF-3 and CBP/p300 to herpes simplex virus ICP0 nuclear foci: potential role in blocking IFN-β induction. Virology 360, 305–321 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Joo, C. H. et al. Inhibition of interferon regulatory factor 7 (IRF7)-mediated interferon signal transduction by the Kaposi's sarcoma-associated herpesvirus viral IRF homolog vIRF3. J. Virol. 81, 8282–8292 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wies, E. et al. The Kaposi's sarcoma-associated herpesvirus-encoded vIRF-3 inhibits cellular IRF-5. J. Biol. Chem. 284, 8525–8538 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Donaghy, H. et al. Role for plasmacytoid dendritic cells in the immune control of recurrent human herpes simplex virus infection. J. Virol. 83, 1952–1961 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Sainz, B., Jr & Halford, W. P. α/β interferon and γ interferon synergize to inhibit the replication of herpes simplex virus type 1. J. Virol. 76, 11541–11550 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Gargano, L. M., Moser, J. M. & Speck, S. H. Role for MyD88 signaling in murine gammaherpesvirus 68 latency. J. Virol. 82, 3853–3863 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Gregory, S. M. et al. Toll-like receptor signaling controls reactivation of KSHV from latency. Proc. Natl Acad. Sci. USA 106, 11725–11730 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Gargano, L. M., Forrest, J. C. & Speck, S. H. Signaling through Toll-like receptors induces murine gammaherpesvirus 68 reactivation in vivo. J. Virol. 83, 1474–1482 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Kristensen, H. et al. Extracellular 2′-5′ oligoadenylate synthetase stimulates RNase L-independent antiviral activity: a novel mechanism of virus-induced innate immunity. J. Virol. 84, 11898–11904 (2010).

    Article  CAS  Google Scholar 

  133. Haahr, S. & Hollsberg, P. Multiple sclerosis is linked to Epstein-Barr virus infection. Rev. Med. Virol. 16, 297–310 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Toussirot, E. & Roudier, J. Epstein-Barr virus in autoimmune diseases. Best Pract. Res. Clin. Rheumatol. 22, 883–896 (2008).

    Article  CAS  PubMed  Google Scholar 

  135. Leadbetter, E. A. et al. Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).

    Article  CAS  PubMed  Google Scholar 

  136. Kimkong, I., Avihingsanon, Y. & Hirankarn, N. Expression profile of HIN200 in leukocytes and renal biopsy of SLE patients by real-time RT-PCR. Lupus 18, 1066–1072 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Mondini, M. et al. Role of the interferon-inducible gene IFI16 in the etiopathogenesis of systemic autoimmune disorders. Ann. NY Acad. Sci. 1110, 47–56 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Casrouge, A. et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314, 308–312 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. Diego, R. P. et al. Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity 33, 400–411 (2010).

    Article  PubMed Central  CAS  Google Scholar 

  140. Ariza, M. E., Glaser, R., Kaumaya, P. T., Jones, C. & Williams, M. V. The EBV-encoded dUTPase activates NF-κB through the TLR2 and MyD88-dependent signaling pathway. J. Immunol. 182, 851–859 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants awarded to S.R.P. from the Danish Medical Research Council (09-072,636), the Lundbeck Foundation (R34-A3855), Velux Fonden, Kathrine og Vigo Skovgaards Fond and Elvira og Rasmus Riisforts almenvelgørende Fond; by grants awarded to K.A.F. from the US National Institutes of Health (AI067497, AI64349, AI083713 and AI079293); and by grants to A.G.B. from Science Foundation Ireland. K.A.H. was supported by a Marie Curie Incoming International Fellowship.

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Authors and Affiliations

  1. Department of Medical Microbiology and Immunology, The Bartholin Building, Aarhus University, DK-8000, Aarhus C, Denmark

    Søren R. Paludan & Kristy A. Horan

  2. School of Biochemistry and Immunology, Trinity College Dublin, 2, Dublin, Ireland

    Andrew G. Bowie

  3. Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Katherine A. Fitzgerald

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Glossary

Lytic infection

Viral replication in host cells either causes cellular death and lysis (lytic infection) or is compatible with cell survival (persistent infection).

Permissive cells

Cells that support the replication of a given virus. Permissiveness is often determined by the expression of specific components in the cells and/or the ability of viruses to circumvent host defence mechanisms.

Latency

A state in which viruses lie dormant in infected cells with no detectable viral replication. From the latent state, viruses can become activated to initiate productive replication.

Pathogen-associated molecular patterns

(PAMPs). Evolutionarily conserved molecular structures that are recognized by pattern recognition receptors. PAMPs are either specific for whole classes of pathogens or used by both microorganism and host but present in abnormal locations.

IFN-stimulated genes

(ISGs). Genes that are induced by interferons (IFNs) through their IFN-stimulated response element (ISRE), which is bound by the IFN-activated transcription factor ISGF3. A subgroup of ISGs is induced by pattern recognition receptor signalling, through transcription factors of the IRF family.

Cross-presentation

The ability of certain antigen-presenting cells (APCs) to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect APCs.

Autophagy

A catabolic process in which cells degrade cytosolic content, including organelles, through the lysosomal machinery.

Pyrin and HIN domain-containing protein family

A family of proteins with both pyrin and HIN domains. Pyrin domains mediate pyrin–pyrin homotypic interactions and stimulate signal transduction, whereas HIN domains bind DNA.

Neurovirulence factor

A factor that is essential for the ability of a pathogen to be pathogenic in the nervous system. Herpes simplex virus and rabies virus are neurovirulent viruses.

Tegument

An amorphous layer of proteins that lines the space between the lipid membrane and the nucleocapsid of herpesviruses. The tegument proteins generally support viral replication and evasion of immune responses.

2′-5′-oligoadenylate synthetase

A family of interferon- and virus-inducible enzymes that catalyses the formation 2′-5′ oligomers of adenosine to stimulate antiviral activities that are dependent and independent of RNase L.

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Paludan, S., Bowie, A., Horan, K. et al. Recognition of herpesviruses by the innate immune system. Nat Rev Immunol 11, 143–154 (2011). https://doi.org/10.1038/nri2937

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