1932

Abstract

DNA viruses are linked to many infectious diseases and contribute significantly to human morbidity and mortality worldwide. Moreover, DNA viral infections are usually lifelong and hard to eradicate. Under certain circumstances, these viruses can cause fatal disease, especially in children and immunocompromised patients. An efficient innate immune response against these viruses is critical, not only as the first line of host defense against viral infection but also for mounting more specific and robust adaptive immunity against the virus. Recognition of the viral DNA genome is the very first step of this whole process and is crucial for understanding viral pathogenesis as well as for preventing and treating DNA virus–associated diseases. This review focuses on the current state of our knowledge on how human DNA viruses are sensed by the host innate immune system and how viral proteins counteract this immune response.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-virology-092917-043244
2018-09-29
2024-05-04
Loading full text...

Full text loading...

/deliver/fulltext/virology/5/1/annurev-virology-092917-043244.html?itemId=/content/journals/10.1146/annurev-virology-092917-043244&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C 2015. Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. J. Clin. Oncol. 33:3235–42
    [Google Scholar]
  2. 2.  Niemann J, Kuhnel F 2017. Oncolytic viruses: adenoviruses. Virus Genes 53:700–6
    [Google Scholar]
  3. 3.  Masrour-Roudsari J, Ebrahimpour S 2017. Causal role of infectious agents in cancer: an overview. Caspian J. Intern. Med. 8:153–58
    [Google Scholar]
  4. 4.  Roizman B, Knipe DM, Whitley RJ 2013. Herpes simplex viruses. Fields Virology DM Knipe, PM Howley 1823–97 Philadelphia: Lippincott Williams & Wilkins. , 6th ed..
    [Google Scholar]
  5. 5.  Gershon AA, Gershon MD 2013. Pathogenesis and current approaches to control of varicella-zoster virus infections. Clin. Microbiol. Rev. 26:728–43
    [Google Scholar]
  6. 6.  Griffiths P, Baraniak I, Reeves M 2015. The pathogenesis of human cytomegalovirus. J. Pathol. 235:288–97
    [Google Scholar]
  7. 7.  Taylor GS, Long HM, Brooks JM, Rickinson AB, Hislop AD 2015. The immunology of Epstein-Barr virus–induced disease. Annu. Rev. Immunol. 33:787–821
    [Google Scholar]
  8. 8.  Dittmer DP, Damania B 2016. Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J. Clin. Investig. 126:3165–75
    [Google Scholar]
  9. 9.  Chan WM, McFadden G 2014. Oncolytic poxviruses. Annu. Rev. Virol. 1:119–41
    [Google Scholar]
  10. 10.  Wu J, Chen ZJ 2014. Innate immune sensing and signaling of cytosolic nucleic acids. Annu. Rev. Immunol. 32:461–88
    [Google Scholar]
  11. 11.  Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG et al. 2004. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. 5:190–98
    [Google Scholar]
  12. 12.  Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S et al. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408:740–45
    [Google Scholar]
  13. 13.  Kim YM, Brinkmann MM, Paquet ME, Ploegh HL 2008. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature 452:234–38
    [Google Scholar]
  14. 14.  Kawai T, Akira S 2011. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–50
    [Google Scholar]
  15. 15.  Hasan UA, Bates E, Takeshita F, Biliato A, Accardi R et al. 2007. TLR9 expression and function is abolished by the cervical cancer-associated human papillomavirus type 16. J. Immunol. 178:3186–97
    [Google Scholar]
  16. 16.  Fiola S, Gosselin D, Takada K, Gosselin J 2010. TLR9 contributes to the recognition of EBV by primary monocytes and plasmacytoid dendritic cells. J. Immunol. 185:3620–31
    [Google Scholar]
  17. 17.  West JA, Gregory SM, Sivaraman V, Su L, Damania B 2011. Activation of plasmacytoid dendritic cells by Kaposi's sarcoma-associated herpesvirus. J. Virol. 85:895–904
    [Google Scholar]
  18. 18.  Shahzad N, Shuda M, Gheit T, Kwun HJ, Cornet I et al. 2013. The T antigen locus of Merkel cell polyomavirus downregulates human Toll-like receptor 9 expression. J. Virol. 87:13009–19
    [Google Scholar]
  19. 19.  Quan TE, Roman RM, Rudenga BJ, Holers VM, Craft JE 2010. Epstein-Barr virus promotes interferon-α production by plasmacytoid dendritic cells. Arthritis Rheum 62:1693–701
    [Google Scholar]
  20. 20.  West J, Damania B 2008. Upregulation of the TLR3 pathway by Kaposi's sarcoma-associated herpesvirus during primary infection. J. Virol. 82:5440–49
    [Google Scholar]
  21. 21.  Boehme KW, Guerrero M, Compton T 2006. Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells. J. Immunol. 177:7094–102
    [Google Scholar]
  22. 22.  Gaudreault E, Fiola S, Olivier M, Gosselin J 2007. Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. J. Virol. 81:8016–24
    [Google Scholar]
  23. 23.  Yew KH, Carpenter C, Duncan RS, Harrison CJ 2012. Human cytomegalovirus induces TLR4 signaling components in monocytes altering TIRAP, TRAM and downstream interferon-beta and TNF-alpha expression. PLOS ONE 7:e44500
    [Google Scholar]
  24. 24.  Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T et al. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5:730–38
    [Google Scholar]
  25. 25.  West JA, Wicks M, Gregory SM, Chugh P, Jacobs SR et al. 2014. An important role for mitochondrial antiviral signaling protein in the Kaposi's sarcoma-associated herpesvirus life cycle. J. Virol. 88:5778–87
    [Google Scholar]
  26. 26.  Rasmussen SB, Jensen SB, Nielsen C, Quartin E, Kato H et al. 2009. Herpes simplex virus infection is sensed by both Toll-like receptors and retinoic acid-inducible gene-like receptors, which synergize to induce type I interferon production. J. Gen. Virol. 90:74–78
    [Google Scholar]
  27. 27.  Samanta M, Iwakiri D, Kanda T, Imaizumi T, Takada K 2006. EB virus-encoded RNAs are recognized by RIG-I and activate signaling to induce type I IFN. EMBO J 25:4207–14
    [Google Scholar]
  28. 28.  Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, Hornung V 2009. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III–transcribed RNA intermediate. Nat. Immunol. 10:1065–72
    [Google Scholar]
  29. 29.  Chiu YH, MacMillan JB, Chen ZJ 2009. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138:576–91
    [Google Scholar]
  30. 30.  Ishikawa H, Barber GN 2008. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455:674–78
    [Google Scholar]
  31. 31.  Zhong B, Yang Y, Li S, Wang YY, Li Y et al. 2008. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29:538–50
    [Google Scholar]
  32. 32.  Sun W, Li Y, Chen L, Chen H, You F et al. 2009. ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. PNAS 106:8653–58
    [Google Scholar]
  33. 33.  Ishikawa H, Ma Z, Barber GN 2009. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–92
    [Google Scholar]
  34. 34.  Abe T, Harashima A, Xia T, Konno H, Konno K et al. 2013. STING recognition of cytoplasmic DNA instigates cellular defense. Mol. Cell 50:5–15
    [Google Scholar]
  35. 35.  Barber GN 2015. STING: infection, inflammation and cancer. Nat. Rev. Immunol. 15:760–70
    [Google Scholar]
  36. 36.  Konno H, Konno K, Barber GN 2013. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155:688–98
    [Google Scholar]
  37. 37.  Ni G, Konno H, Barber GN 2017. Ubiquitination of STING at lysine 224 controls IRF3 activation. Sci. Immunol. 2:eaah7119
    [Google Scholar]
  38. 38.  Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T et al. 2009. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. PNAS 106:20842–46
    [Google Scholar]
  39. 39.  Liu S, Cai X, Wu J, Cong Q, Chen X et al. 2015. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347:aaa2630
    [Google Scholar]
  40. 40.  Tanaka Y, Chen ZJ 2012. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci. Signal. 5:ra20
    [Google Scholar]
  41. 41.  Ma Z, Damania B 2016. The cGAS-STING defense pathway and its counteraction by viruses. Cell Host Microbe 19:150–58
    [Google Scholar]
  42. 42.  Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B et al. 2011. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478:515–18
    [Google Scholar]
  43. 43.  Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB et al. 2010. IFI16 is an innate immune sensor for intracellular DNA. Nat. Immunol. 11:997–1004
    [Google Scholar]
  44. 44.  Horan KA, Hansen K, Jakobsen MR, Holm CK, Søby S et al. 2013. Proteasomal degradation of herpes simplex virus capsids in macrophages releases DNA to the cytosol for recognition by DNA sensors. J. Immunol. 190:2311–19
    [Google Scholar]
  45. 45.  Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu YJ 2011. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat. Immunol. 12:959–65
    [Google Scholar]
  46. 46.  Parvatiyar K, Zhang Z, Teles RM, Ouyang S, Jiang Y et al. 2012. The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat. Immunol. 13:1155–61
    [Google Scholar]
  47. 47.  Sun L, Wu J, Du F, Chen X, Chen ZJ 2013. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–91
    [Google Scholar]
  48. 48.  Ferguson BJ, Mansur DS, Peters NE, Ren H, Smith GL 2012. DNA-PK is a DNA sensor for IRF-3-dependent innate immunity. eLife 1:e00047
    [Google Scholar]
  49. 49.  Wang J, Kang L, Song D, Liu L, Yang S et al. 2017. Ku70 senses HTLV-1 DNA and modulates HTLV-1 replication. J. Immunol. 199:2475–82
    [Google Scholar]
  50. 50.  Kondo T, Kobayashi J, Saitoh T, Maruyama K, Ishii KJ et al. 2013. DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking. PNAS 110:2969–74
    [Google Scholar]
  51. 51.  Wu J, Sun L, Chen X, Du F, Shi H et al. 2013. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339:826–30
    [Google Scholar]
  52. 52.  Ouyang S, Song X, Wang Y, Ru H, Shaw N et al. 2012. Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding. Immunity 36:1073–86
    [Google Scholar]
  53. 53.  Gao P, Ascano M, Zillinger T, Wang W, Dai P et al. 2013. Structure-function analysis of STING activation by c[G(2′,5′)pA(3′,5′)p] and targeting by antiviral DMXAA. Cell 154:748–62
    [Google Scholar]
  54. 54.  Zhang X, Shi H, Wu J, Zhang X, Sun L et al. 2013. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51:226–35
    [Google Scholar]
  55. 55.  Chen Q, Sun L, Chen ZJ 2016. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat. Immunol. 17:1142–49
    [Google Scholar]
  56. 56.  Li XD, Wu J, Gao D, Wang H, Sun L, Chen ZJ 2013. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341:1390–94
    [Google Scholar]
  57. 57.  Schoggins JW, MacDuff DA, Imanaka N, Gainey MD, Shrestha B et al. 2014. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505:691–95
    [Google Scholar]
  58. 58.  Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T et al. 2013. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503:530–34
    [Google Scholar]
  59. 59.  Liang Q, Seo GJ, Choi YJ, Ge J, Rodgers MA et al. 2014. Autophagy side of MB21D1/cGAS DNA sensor. Autophagy 10:1146–47
    [Google Scholar]
  60. 60.  Liang Q, Seo GJ, Choi YJ, Kwak MJ, Ge J et al. 2014. Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15:228–38
    [Google Scholar]
  61. 61.  Kanneganti TD 2010. Central roles of NLRs and inflammasomes in viral infection. Nat. Rev. Immunol. 10:688–98
    [Google Scholar]
  62. 62.  Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES 2009. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458:509–13
    [Google Scholar]
  63. 63.  Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G et al. 2009. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458:514–18
    [Google Scholar]
  64. 64.  Bürckstümmer T, Baumann C, Blüml S, Dixit E, Dürnberger G et al. 2009. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat. Immunol. 10:266–72
    [Google Scholar]
  65. 65.  Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM et al. 2009. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323:1057–60
    [Google Scholar]
  66. 66.  Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE et al. 2010. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11:395–402
    [Google Scholar]
  67. 67.  Fernandes-Alnemri T, Yu JW, Juliana C, Solorzano L, Kang S et al. 2010. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat. . Immunol 11:385–93
    [Google Scholar]
  68. 68.  Dell'Oste V, Gatti D, Giorgio AG, Gariglio M, Landolfo S, De Andrea M 2015. The interferon-inducible DNA-sensor protein IFI16: a key player in the antiviral response. New Microbiol 38:5–20
    [Google Scholar]
  69. 69.  Diner BA, Lum KK, Cristea IM 2015. The emerging role of nuclear viral DNA sensors. J. Biol. Chem. 290:26412–21
    [Google Scholar]
  70. 70.  Monroe KM, Yang Z, Johnson JR, Geng X, Doitsh G et al. 2014. IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV. Science 343:428–32
    [Google Scholar]
  71. 71.  Jakobsen MR, Bak RO, Andersen A, Berg RK, Jensen SB et al. 2013. IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication. PNAS 110:E4571–80
    [Google Scholar]
  72. 72.  Delaloye J, Roger T, Steiner-Tardivel QG, Le Roy D, Knaup Reymond M et al. 2009. Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. PLOS Pathog 5:e1000480
    [Google Scholar]
  73. 73.  Muruve DA, Petrilli V, Zaiss AK, White LR, Clark SA et al. 2008. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452:103–7
    [Google Scholar]
  74. 74.  Nour AM, Reichelt M, Ku CC, Ho MY, Heineman TC, Arvin AM 2011. Varicella-zoster virus infection triggers formation of an interleukin-1β (IL-1β)-processing inflammasome complex. J. Biol. Chem. 286:17921–33
    [Google Scholar]
  75. 75.  Gregory SM, Davis BK, West JA, Taxman DJ, Matsuzawa S et al. 2011. Discovery of a viral NLR homolog that inhibits the inflammasome. Science 331:330–34
    [Google Scholar]
  76. 76.  Ma Z, Hopcraft SE, Yang F, Petrucelli A, Guo H et al. 2017. NLRX1 negatively modulates type I IFN to facilitate KSHV reactivation from latency. PLOS Pathog 13:e1006350
    [Google Scholar]
  77. 77.  Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H et al. 2007. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448:501–5
    [Google Scholar]
  78. 78.  DeFilippis VR, Alvarado D, Sali T, Rothenburg S, Früh K 2010. Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1. J. Virol. 84:585–98
    [Google Scholar]
  79. 79.  Ishii KJ, Kawagoe T, Koyama S, Matsui K, Kumar H et al. 2008. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature 451:725–29
    [Google Scholar]
  80. 80.  Kim T, Pazhoor S, Bao M, Zhang Z, Hanabuchi S et al. 2010. Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells. PNAS 107:15181–86
    [Google Scholar]
  81. 81.  Barton GM, Kagan JC, Medzhitov R 2006. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat. Immunol. 7:49–56
    [Google Scholar]
  82. 82.  Mouchess ML, Arpaia N, Souza G, Barbalat R, Ewald SE et al. 2011. Transmembrane mutations in Toll-like receptor 9 bypass the requirement for ectodomain proteolysis and induce fatal inflammation. Immunity 35:721–32
    [Google Scholar]
  83. 83.  Rathinam VA, Fitzgerald KA 2011. Innate immune sensing of DNA viruses. Virology 411:153–62
    [Google Scholar]
  84. 84.  Pohar J, Kuznik Krajnik A, Jerala R, Bencina M 2015. Minimal sequence requirements for oligodeoxyribonucleotides activating human TLR9. J. Immunol. 194:3901–8
    [Google Scholar]
  85. 85.  Pohar J, Lainscek D, Ivicak-Kocjan K, Cajnko MM, Jerala R, Bencina M 2017. Short single-stranded DNA degradation products augment the activation of Toll-like receptor 9. Nat. Commun. 8:15363
    [Google Scholar]
  86. 86.  Rigby RE, Webb LM, Mackenzie KJ, Li Y, Leitch A et al. 2014. RNA:DNA hybrids are a novel molecular pattern sensed by TLR9. EMBO J 33:542–58
    [Google Scholar]
  87. 87.  Civril F, Deimling T, de Oliveira Mann CC, Ablasser A, Moldt M et al. 2013. Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498:332–37
    [Google Scholar]
  88. 88.  Kato K, Ishii R, Goto E, Ishitani R, Tokunaga F, Nureki O 2013. Structural and functional analyses of DNA-sensing and immune activation by human cGAS. PLOS ONE 8:e76983
    [Google Scholar]
  89. 89.  Kranzusch PJ, Lee AS, Berger JM, Doudna JA 2013. Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity. Cell Rep 3:1362–68
    [Google Scholar]
  90. 90.  Gao D, Li T, Li XD, Chen X, Li QZ et al. 2015. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. PNAS 112:E5699–705
    [Google Scholar]
  91. 91.  Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V 2014. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J. Immunol. 192:5993–97
    [Google Scholar]
  92. 92.  Ahn J, Ruiz P, Barber GN 2014. Intrinsic self-DNA triggers inflammatory disease dependent on STING. J. Immunol. 193:4634–42
    [Google Scholar]
  93. 93.  Steinhagen F, Zillinger T, Peukert K, Fox M, Thudium M et al. 2018. Suppressive oligodeoxynucleotides containing TTAGGG motifs inhibit cGAS activation in human monocytes. Eur. J. Immunol. 48:605–11
    [Google Scholar]
  94. 94.  Bayik D, Gursel I, Klinman DM 2016. Structure, mechanism and therapeutic utility of immunosuppressive oligonucleotides. Pharmacol. Res. 105:216–25
    [Google Scholar]
  95. 95.  Mankan AK, Schmidt T, Chauhan D, Goldeck M, Honing K et al. 2014. Cytosolic RNA:DNA hybrids activate the cGAS-STING axis. EMBO J 33:2937–46
    [Google Scholar]
  96. 96.  Jin T, Perry A, Jiang J, Smith P, Curry JA et al. 2012. Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity 36:561–71
    [Google Scholar]
  97. 97.  Ni X, Ru H, Ma F, Zhao L, Shaw N et al. 2016. New insights into the structural basis of DNA recognition by HINa and HINb domains of IFI16. J. Mol. Cell Biol. 8:51–61
    [Google Scholar]
  98. 98.  Yan H, Dalal K, Hon BK, Youkharibache P, Lau D, Pio F 2008. RPA nucleic acid-binding properties of IFI16-HIN200. Biochim. Biophys. Acta 1784:1087–97
    [Google Scholar]
  99. 99.  Brazda V, Coufal J, Liao JC, Arrowsmith CH 2012. Preferential binding of IFI16 protein to cruciform structure and superhelical DNA. Biochem. Biophys. Res. Commun. 422:716–20
    [Google Scholar]
  100. 100.  Murat P, Zhong J, Lekieffre L, Cowieson NP, Clancy JL et al. 2014. G-quadruplexes regulate Epstein-Barr virus-encoded nuclear antigen 1 mRNA translation. Nat. Chem. Biol. 10:358–64
    [Google Scholar]
  101. 101.  Piekna-Przybylska D, Sullivan MA, Sharma G, Bambara RA 2014. U3 region in the HIV-1 genome adopts a G-quadruplex structure in its RNA and DNA sequence. Biochemistry 53:2581–93
    [Google Scholar]
  102. 102.  Wang Y, Patel DJ 1993. Solution structure of a parallel-stranded G-quadruplex DNA. J. Mol. Biol. 234:1171–83
    [Google Scholar]
  103. 103.  Kaminski JJ, Schattgen SA, Tzeng TC, Bode C, Klinman DM, Fitzgerald KA 2013. Synthetic oligodeoxynucleotides containing suppressive TTAGGG motifs inhibit AIM2 inflammasome activation. J. Immunol. 191:3876–83
    [Google Scholar]
  104. 104.  Dempsey A, Bowie AG 2015. Innate immune recognition of DNA: a recent history. Virology 479–80:146–52
    [Google Scholar]
  105. 105.  Lee KG, Kim SS, Kui L, Voon DC, Mauduit M et al. 2015. Bruton's tyrosine kinase phosphorylates DDX41 and activates its binding of dsDNA and STING to initiate type 1 interferon response. Cell Rep 10:1055–65
    [Google Scholar]
  106. 106.  Jiang Y, Zhu Y, Qiu W, Liu YJ, Cheng G et al. 2017. Structural and functional analyses of human DDX41 DEAD domain. Protein Cell 8:72–76
    [Google Scholar]
  107. 107.  Cario E 2008. Barrier-protective function of intestinal epithelial Toll-like receptor 2. Mucosal Immunol 1:Suppl. 1S62–66
    [Google Scholar]
  108. 108.  Iwasaki A 2010. Antiviral immune responses in the genital tract: clues for vaccines. Nat. Rev. Immunol. 10:699–711
    [Google Scholar]
  109. 109.  Kijpittayarit S, Eid AJ, Brown RA, Paya CV, Razonable RR 2007. Relationship between Toll-like receptor 2 polymorphism and cytomegalovirus disease after liver transplantation. Clin. Infect. Dis. 44:1315–20
    [Google Scholar]
  110. 110.  Carty M, Bowie AG 2010. Recent insights into the role of Toll-like receptors in viral infection. Clin. Exp. Immunol. 161:397–406
    [Google Scholar]
  111. 111.  Hutchens MA, Luker KE, Sonstein J, Nunez G, Curtis JL, Luker GD 2008. Protective effect of Toll-like receptor 4 in pulmonary vaccinia infection. PLOS Pathog 4:e1000153
    [Google Scholar]
  112. 112.  Smith AE, Helenius A 2004. How viruses enter animal cells. Science 304:237–42
    [Google Scholar]
  113. 113.  Dimitrov DS 2004. Virus entry: molecular mechanisms and biomedical applications. Nat. Rev. Microbiol. 2:109–22
    [Google Scholar]
  114. 114.  Leifer CA, Kennedy MN, Mazzoni A, Lee C, Kruhlak MJ, Segal DM 2004. TLR9 is localized in the endoplasmic reticulum prior to stimulation. J. Immunol. 173:1179–83
    [Google Scholar]
  115. 115.  Hacker H, Mischak H, Miethke T, Liptay S, Schmid R et al. 1998. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J 17:6230–40
    [Google Scholar]
  116. 116.  Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi GP et al. 2008. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456:658–62
    [Google Scholar]
  117. 117.  Park B, Brinkmann MM, Spooner E, Lee CC, Kim YM, Ploegh HL 2008. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat. Immunol. 9:1407–14
    [Google Scholar]
  118. 118.  Sepulveda FE, Maschalidi S, Colisson R, Heslop L, Ghirelli C et al. 2009. Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells. Immunity 31:737–48
    [Google Scholar]
  119. 119.  Ewald SE, Engel A, Lee J, Wang M, Bogyo M, Barton GM 2011. Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase. J. Exp. Med. 208:643–51
    [Google Scholar]
  120. 120.  Xu RH, Wong EB, Rubio D, Roscoe F, Ma X et al. 2015. Sequential activation of two pathogen-sensing pathways required for type I interferon expression and resistance to an acute DNA virus infection. Immunity 43:1148–59
    [Google Scholar]
  121. 121.  Spooner RA, Smith DC, Easton AJ, Roberts LM, Lord JM 2006. Retrograde transport pathways utilised by viruses and protein toxins. Virol. J. 3:26
    [Google Scholar]
  122. 122.  West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM et al. 2015. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520:553–57
    [Google Scholar]
  123. 123.  White MJ, McArthur K, Metcalf D, Lane RM, Cambier JC et al. 2014. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159:1549–62
    [Google Scholar]
  124. 124.  Rongvaux A, Jackson R, Harman CC, Li T, West AP et al. 2014. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159:1563–77
    [Google Scholar]
  125. 125.  Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N et al. 2012. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36:401–14
    [Google Scholar]
  126. 126.  Sui H, Zhou M, Imamichi H, Jiao X, Sherman BT et al. 2017. STING is an essential mediator of the Ku70-mediated production of IFN-λ1 in response to exogenous DNA. Sci. Signal. 10:eaah5054
    [Google Scholar]
  127. 127.  Orzalli MH, Broekema NM, Diner BA, Hancks DC, Elde NC et al. 2015. cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection. PNAS 112:E1773–81
    [Google Scholar]
  128. 128.  Yang H, Wang H, Ren J, Chen Q, Chen ZJ 2017. cGAS is essential for cellular senescence. PNAS 114:E4612–20
    [Google Scholar]
  129. 129.  Biolatti M, Dell'Oste V, Pautasso S, von Einem J, Marschall M et al. 2016. Regulatory interaction between the cellular restriction factor IFI16 and viral pp65 (pUL83) modulates viral gene expression and IFI16 protein stability. J. Virol. 90:8238–50
    [Google Scholar]
  130. 130.  Li T, Chen J, Cristea IM 2013. Human cytomegalovirus tegument protein pUL83 inhibits IFI16-mediated DNA sensing for immune evasion. Cell Host Microbe 14:591–99
    [Google Scholar]
  131. 131.  Cristea IM, Moorman NJ, Terhune SS, Cuevas CD, O'Keefe ES et al. 2010. Human cytomegalovirus pUL83 stimulates activity of the viral immediate-early promoter through its interaction with the cellular IFI16 protein. J. Virol. 84:7803–14
    [Google Scholar]
  132. 132.  Dell'Oste V, Gatti D, Gugliesi F, De Andrea M, Bawadekar M et al. 2014. Innate nuclear sensor IFI16 translocates into the cytoplasm during the early stage of in vitro human cytomegalovirus infection and is entrapped in the egressing virions during the late stage. J. Virol. 88:6970–82
    [Google Scholar]
  133. 133.  Kalamvoki M, Du T, Roizman B 2014. Cells infected with herpes simplex virus 1 export to uninfected cells exosomes containing STING, viral mRNAs, and microRNAs. PNAS 111:E4991–96
    [Google Scholar]
  134. 134.  Wu JJ, Li W, Shao Y, Avey D, Fu B et al. 2015. Inhibition of cGAS DNA sensing by a herpesvirus virion protein. Cell Host Microbe 18:333–44
    [Google Scholar]
  135. 135.  Peters NE, Ferguson BJ, Mazzon M, Fahy AS, Krysztofinska E et al. 2013. A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus. PLOS Pathog 9:e1003649
    [Google Scholar]
  136. 136.  Stack J, Haga IR, Schroder M, Bartlett NW, Maloney G et al. 2005. Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. J. Exp. Med. 201:1007–18
    [Google Scholar]
  137. 137.  Ma Z, Jacobs SR, West JA, Stopford C, Zhang Z et al. 2015. Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. PNAS 112:E4306–15
    [Google Scholar]
  138. 138.  Jacobs SR, Damania B 2012. NLRs, inflammasomes, and viral infection. J. Leukoc. Biol. 92:469–77
    [Google Scholar]
  139. 139.  Johnston JB, Barrett JW, Nazarian SH, Goodwin M, Ricciuto D et al. 2005. A poxvirus-encoded pyrin domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection. Immunity 23:587–98
    [Google Scholar]
  140. 140.  Stehlik C, Krajewska M, Welsh K, Krajewski S, Godzik A, Reed JC 2003. The PAAD/PYRIN-only protein POP1/ASC2 is a modulator of ASC-mediated nuclear-factor-κB and pro-caspase-1 regulation. Biochem. J. 373:101–13
    [Google Scholar]
  141. 141.  Liu Y, Li J, Chen J, Li Y, Wang W et al. 2015. Hepatitis B virus polymerase disrupts K63-linked ubiquitination of STING to block innate cytosolic DNA-sensing pathways. J. Virol. 89:2287–300
    [Google Scholar]
  142. 142.  Inn KS, Lee SH, Rathbun JY, Wong LY, Toth Z et al. 2011. Inhibition of RIG-I-mediated signaling by Kaposi's sarcoma-associated herpesvirus-encoded deubiquitinase ORF64. J. Virol. 85:10899–904
    [Google Scholar]
  143. 143.  Orzalli MH, DeLuca NA, Knipe DM 2012. Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein. PNAS 109:E3008–17
    [Google Scholar]
  144. 144.  Cuchet-Lourenco D, Anderson G, Sloan E, Orr A, Everett RD 2013. The viral ubiquitin ligase ICP0 is neither sufficient nor necessary for degradation of the cellular DNA sensor IFI16 during herpes simplex virus 1 infection. J. Virol. 87:13422–32
    [Google Scholar]
  145. 145.  Diner BA, Lum KK, Javitt A, Cristea IM 2015. Interactions of the antiviral factor interferon gamma-inducible protein 16 (IFI16) mediate immune signaling and herpes simplex virus-1 immunosuppression. Mol. Cell. Proteom. 14:2341–56
    [Google Scholar]
  146. 146.  Kalamvoki M, Roizman B 2014. HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation. PNAS 111:E611–17
    [Google Scholar]
  147. 147.  Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL et al. 2013. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+ T cells and successful immunotherapy against chronic viral liver infection. Nat. Immunol. 14:574–83
    [Google Scholar]
  148. 148.  Guo F, Han Y, Zhao X, Wang J, Liu F et al. 2015. STING agonists induce an innate antiviral immune response against hepatitis B virus. Antimicrob. Agents Chemother. 59:1273–81
    [Google Scholar]
  149. 149.  Grivennikov SI, Greten FR, Karin M 2010. Immunity, inflammation, and cancer. Cell 140:883–99
    [Google Scholar]
  150. 150.  Krieg AM 2008. Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 27:161–67
    [Google Scholar]
  151. 151.  Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ et al. 2014. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830–42
    [Google Scholar]
  152. 152.  Deng L, Liang H, Xu M, Yang X, Burnette B et al. 2014. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41:843–52
    [Google Scholar]
  153. 153.  Ng KW, Marshall EA, Bell JC, Lam WL 2017. cGAS-STING and cancer: dichotomous roles in tumor immunity and development. Trends Immunol 39:44–54
    [Google Scholar]
  154. 154.  Gao D, Wu J, Wu YT, Du F, Aroh C et al. 2013. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341:903–6
    [Google Scholar]
  155. 155.  Engels EA, Biggar RJ, Hall HI, Cross H, Crutchfield A et al. 2008. Cancer risk in people infected with human immunodeficiency virus in the United States. Int. J. Cancer 123:187–94
    [Google Scholar]
  156. 156.  Herzner AM, Hagmann CA, Goldeck M, Wolter S, Kubler K et al. 2015. Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA. Nat. Immunol. 16:1025–33
    [Google Scholar]
  157. 157.  Horton NC, Finzel BC 1996. The structure of an RNA/DNA hybrid: a substrate of the ribonuclease activity of HIV-1 reverse transcriptase. J. Mol. Biol. 264:521–33
    [Google Scholar]
  158. 158.  Du X, Poltorak A, Wei Y, Beutler B 2000. Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur. Cytokine Netw. 11:362–71
    [Google Scholar]
  159. 159.  Chuang TH, Ulevitch RJ 2000. Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. Eur. Cytokine Netw. 11:372–78
    [Google Scholar]
  160. 160.  Zhang G, Chan B, Samarina N, Abere B, Weidner-Glunde M et al. 2016. Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS. PNAS 113:E1034–43
    [Google Scholar]
  161. 161.  Lau L, Gray EE, Brunette RL, Stetson DB 2015. DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway. Science 350:568–71
    [Google Scholar]
  162. 162.  Sun C, Schattgen SA, Pisitkun P, Jorgensen JP, Hilterbrand AT et al. 2015. Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection. J. Immunol. 194:1819–31
    [Google Scholar]
/content/journals/10.1146/annurev-virology-092917-043244
Loading
/content/journals/10.1146/annurev-virology-092917-043244
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error