1887

Abstract

Viruses that establish persistent infections have evolved numerous strategies to evade host innate antiviral responses. We functionally assessed the role of herpes simplex virus type 2 (HSV-2) virion host shutoff (vhs) protein on innate immune sensing pathways in human vaginal epithelial cells (VK2 ECs). Infection of cells with wild-type (WT) HSV-2 significantly decreased expression of innate immune sensors of viral infection, Toll-like receptor (TLR)2, TLR3, retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda-5), relative to cells infected with a mutant that lacks vhs (vhsB) or mock-infected cells. Transfection with HSV-2 vhs similarly decreased expression of TLR2, TLR3, RIG-I and Mda-5, which was also confirmed in human embryonic kidney (HEK) 293 cells. vhsB infection of VK2 cells caused robust increases in the active form of interferon regulatory factor (IRF)3 and its translocation to the nucleus compared with the WT. Additionally, IRF3 activation by Sendai virus and polyinosinic : polycytidylic acid-induced stimulation of beta interferon (IFN-β) was significantly inhibited in vhs-transfected cells. Overall, our findings provide the first evidence that HSV-2 vhs plays roles in selectively inhibiting TLR3 and RIG-I/Mda-5, as well as TLR2-mediated antiviral pathways for sensing dsRNA and effectively suppresses IFN-β antiviral responses in human vaginal ECs.

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2011-09-01
2024-03-28
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References

  1. Amici C., Rossi A., Costanzo A., Ciafrè S., Marinari B., Balsamo M., Levrero M., Santoro M. G. 2006; Herpes simplex virus disrupts NF-κB regulation by blocking its recruitment on the IκBα promoter and directing the factor on viral genes. J Biol Chem 281:7110–7117 [View Article][PubMed]
    [Google Scholar]
  2. Andersen J. M., Al-Khairy D., Ingalls R. R. 2006; Innate immunity at the mucosal surface: role of toll-like receptor 3 and toll-like receptor 9 in cervical epithelial cell responses to microbial pathogens. Biol Reprod 74:824–831 [View Article][PubMed]
    [Google Scholar]
  3. Ashkar A. A., Yao X. D., Gill N., Sajic D., Patrick A. J., Rosenthal K. L. 2004; Toll-like receptor (TLR)-3, but not TLR4, agonist protects against genital herpes infection in the absence of inflammation seen with CpG DNA. J Infect Dis 190:1841–1849 [View Article][PubMed]
    [Google Scholar]
  4. Barbalat R., Lau L., Locksley R. M., Barton G. M. 2009; Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands. Nat Immunol 10:1200–1207 [View Article][PubMed]
    [Google Scholar]
  5. Bauernfeind F., Hornung V. 2009; TLR2 joins the interferon gang. Nat Immunol 10:1139–1141 [View Article][PubMed]
    [Google Scholar]
  6. Bochud P. Y., Magaret A. S., Koelle D. M., Aderem A., Wald A. 2007; 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 [View Article][PubMed]
    [Google Scholar]
  7. Chee A. V., Roizman B. 2004; Herpes simplex virus 1 gene products occlude the interferon signaling pathway at multiple sites. J Virol 78:4185–4196 [View Article][PubMed]
    [Google Scholar]
  8. Doepker R. C., Hsu W. L., Saffran H. A., Smiley J. R. 2004; Herpes simplex virus virion host shutoff protein is stimulated by translation initiation factors eIF4B and eIF4H. J Virol 78:4684–4699 [View Article][PubMed]
    [Google Scholar]
  9. Duerst R. J., Morrison L. A. 2004; Herpes simplex virus 2 virion host shutoff protein interferes with type I interferon production and responsiveness. Virology 322:158–167 [View Article][PubMed]
    [Google Scholar]
  10. Eisemann J., Mühl-Zürbes P., Steinkasserer A., Kummer M. 2007; Infection of mature dendritic cells with herpes simplex virus type 1 interferes with the interferon signaling pathway. Immunobiology 212:877–886 [View Article][PubMed]
    [Google Scholar]
  11. Elco C. P., Guenther J. M., Williams B. R., Sen G. C. 2005; Analysis of genes induced by Sendai virus infection of mutant cell lines reveals essential roles of interferon regulatory factor 3, NF-κB, and interferon but not toll-like receptor 3. J Virol 79:3920–3929 [View Article][PubMed]
    [Google Scholar]
  12. Everly D. N. Jr, Read G. S. 1997; Mutational analysis of the virion host shutoff gene (UL41) of herpes simplex virus (HSV): characterization of HSV type 1 (HSV-1)/HSV-2 chimeras. J Virol 71:7157–7166[PubMed]
    [Google Scholar]
  13. Fakioglu E., Wilson S. S., Mesquita P. M., Hazrati E., Cheshenko N., Blaho J. A., Herold B. C. 2008; Herpes simplex virus downregulates secretory leukocyte protease inhibitor: a novel immune evasion mechanism. J Virol 82:9337–9344 [View Article][PubMed]
    [Google Scholar]
  14. Feng P., Everly D. N. Jr, Read G. S. 2005; mRNA decay during herpes simplex virus (HSV) infections: protein-protein interactions involving the HSV virion host shutoff protein and translation factors eIF4H and eIF4A. J Virol 79:9651–9664 [View Article][PubMed]
    [Google Scholar]
  15. Finberg R. W., Wang J. P., Kurt-Jones E. A. 2007; Toll like receptors and viruses. Rev Med Virol 17:35–43 [View Article][PubMed]
    [Google Scholar]
  16. Finlay B. B., McFadden G. 2006; Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell 124:767–782 [View Article][PubMed]
    [Google Scholar]
  17. Gill N., Deacon P. M., Lichty B., Mossman K. L., Ashkar A. A. 2006; Induction of innate immunity against herpes simplex virus type 2 infection via local delivery of Toll-like receptor ligands correlates with beta interferon production. J Virol 80:9943–9950 [View Article][PubMed]
    [Google Scholar]
  18. Guo J., Peters K. L., Sen G. C. 2000; Induction of the human protein P56 by interferon, double-stranded RNA, or virus infection. Virology 267:209–219 [View Article][PubMed]
    [Google Scholar]
  19. Hardwicke M. A., Sandri-Goldin R. M. 1994; The herpes simplex virus regulatory protein ICP27 contributes to the decrease in cellular mRNA levels during infection. J Virol 68:4797–4810[PubMed]
    [Google Scholar]
  20. Hargett D., Rice S., Bachenheimer S. L. 2006; Herpes simplex virus type 1 ICP27-dependent activation of NF-κB. J Virol 80:10565–10578 [View Article][PubMed]
    [Google Scholar]
  21. Honda K., Taniguchi T. 2006; IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 6:644–658 [View Article][PubMed]
    [Google Scholar]
  22. Honda K., Yanai H., Negishi H., Asagiri M., Sato M., Mizutani T., Shimada N., Ohba Y., Takaoka A. et al. 2005; IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434:772–777 [View Article][PubMed]
    [Google Scholar]
  23. Korom M., Wylie K. M., Morrison L. A. 2008; Selective ablation of virion host shutoff protein RNase activity attenuates herpes simplex virus 2 in mice. J Virol 82:3642–3653 [View Article][PubMed]
    [Google Scholar]
  24. Krug A., Luker G. D., Barchet W., Leib D. A., Akira S., Colonna M. 2004; Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood 103:1433–1437 [View Article][PubMed]
    [Google Scholar]
  25. Kurt-Jones E. A., Chan M., Zhou S., Wang J., Reed G., Bronson R., Arnold M. M., Knipe D. M., Finberg R. W. 2004; Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. Proc Natl Acad Sci U S A 101:1315–1320 [View Article][PubMed]
    [Google Scholar]
  26. Kurt-Jones E. A., Belko J., Yu C., Newburger P. E., Wang J., Chan M., Knipe D. M., Finberg R. W. 2005; The role of toll-like receptors in herpes simplex infection in neonates. J Infect Dis 191:746–748 [View Article][PubMed]
    [Google Scholar]
  27. Kwong A. D., Frenkel N. 1987; Herpes simplex virus-infected cells contain a function(s) that destabilizes both host and viral mRNAs. Proc Natl Acad Sci U S A 84:1926–1930 [View Article][PubMed]
    [Google Scholar]
  28. Lin R., Noyce R. S., Collins S. E., Everett R. D., Mossman K. L. 2004; The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferon-stimulated genes. J Virol 78:1675–1684 [View Article][PubMed]
    [Google Scholar]
  29. Liu X., Fitzgerald K., Kurt-Jones E., Finberg R., Knipe D. M. 2008; Herpesvirus tegument protein activates NF-κB signaling through the TRAF6 adaptor protein. Proc Natl Acad Sci U S A 105:11335–11339 [View Article][PubMed]
    [Google Scholar]
  30. Lund J., Sato A., Akira S., Medzhitov R., Iwasaki A. 2003; Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 198:513–520 [View Article][PubMed]
    [Google Scholar]
  31. Melchjorsen J., Sirén J., Julkunen I., Paludan S. R., Matikainen S. 2006; 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 [View Article][PubMed]
    [Google Scholar]
  32. Melroe G. T., DeLuca N. A., Knipe D. M. 2004; Herpes simplex virus 1 has multiple mechanisms for blocking virus-induced interferon production. J Virol 78:8411–8420 [View Article][PubMed]
    [Google Scholar]
  33. Nasu K., Itoh H., Yuge A., Nishida M., Narahara H. 2007; Human oviductal epithelial cells express Toll-like receptor 3 and respond to double-stranded RNA: fallopian tube-specific mucosal immunity against viral infection. Hum Reprod 22:356–361 [View Article][PubMed]
    [Google Scholar]
  34. Paladino P., Collins S. E., Mossman K. L. 2010; Cellular localization of the herpes simplex virus ICP0 protein dictates its ability to block IRF3-mediated innate immune responses. PLoS ONE 5:e10428 [View Article][PubMed]
    [Google Scholar]
  35. Paludan S. R. 2001; Requirements for the induction of interleukin-6 by herpes simplex virus-infected leukocytes. J Virol 75:8008–8015 [View Article][PubMed]
    [Google Scholar]
  36. Pasieka T. J., Lu B., Crosby S. D., Wylie K. M., Morrison L. A., Alexander D. E., Menachery V. D., Leib D. A. 2008; Herpes simplex virus virion host shutoff attenuates establishment of the antiviral state. J Virol 82:5527–5535 [View Article][PubMed]
    [Google Scholar]
  37. Pasieka T. J., Cilloniz C., Lu B., Teal T. H., Proll S. C., Katze M. G., Leib D. A. 2009; Host responses to wild-type and attenuated herpes simplex virus infection in the absence of Stat1. J Virol 83:2075–2087 [View Article][PubMed]
    [Google Scholar]
  38. Patel A., Hanson J., McLean T. I., Olgiate J., Hilton M., Miller W. E., Bachenheimer S. L. 1998; Herpes simplex type 1 induction of persistent NF-κB nuclear translocation increases the efficiency of virus replication. Virology 247:212–222 [View Article][PubMed]
    [Google Scholar]
  39. Peng T., Zhu J., Klock A., Phasouk K., Huang M. L., Koelle D. M., Wald A., Corey L. 2009; Evasion of the mucosal innate immune system by herpes simplex virus type 2. J Virol 83:12559–12568 [View Article][PubMed]
    [Google Scholar]
  40. Pichlmair A., Reis e Sousa C. 2007; Innate recognition of viruses. Immunity 27:370–383 [View Article][PubMed]
    [Google Scholar]
  41. Reszka N. J., Dudek T., Knipe D. M. 2010; Construction and properties of a herpes simplex virus 2 dl5-29 vaccine candidate strain encoding an HSV-1 virion host shutoff protein. Vaccine 28:2754–2762 [View Article][PubMed]
    [Google Scholar]
  42. Saffran H. A., Read G. S., Smiley J. R. 2010; Evidence for translational regulation by the herpes simplex virus virion host shutoff protein. J Virol 84:6041–6049 [View Article][PubMed]
    [Google Scholar]
  43. Saira K., Zhou Y., Jones C. 2007; The infected cell protein 0 encoded by bovine herpesvirus 1 (bICP0) induces degradation of interferon response factor 3 and, consequently, inhibits beta interferon promoter activity. J Virol 81:3077–3086 [View Article][PubMed]
    [Google Scholar]
  44. Samady L., Costigliola E., MacCormac L., McGrath Y., Cleverley S., Lilley C. E., Smith J., Latchman D. S., Chain B., Coffin R. S. 2003; Deletion of the virion host shutoff protein (vhs) from herpes simplex virus (HSV) relieves the viral block to dendritic cell activation: potential of vhs-HSV vectors for dendritic cell-mediated immunotherapy. J Virol 77:3768–3776 [View Article][PubMed]
    [Google Scholar]
  45. Sarma N., Agarwal D., Shiflett L. A., Read G. S. 2008; Small interfering RNAs that deplete the cellular translation factor eIF4H impede mRNA degradation by the virion host shutoff protein of herpes simplex virus. J Virol 82:6600–6609 [View Article][PubMed]
    [Google Scholar]
  46. Sato M., Suemori H., Hata N., Asagiri M., Ogasawara K., Nakao K., Nakaya T., Katsuki M., Noguchi S. et al. 2000; Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-α/β gene induction. Immunity 13:539–548 [View Article][PubMed]
    [Google Scholar]
  47. Smiley J. R. 2004; Herpes simplex virus virion host shutoff protein: immune evasion mediated by a viral RNase?. J Virol 78:1063–1068 [View Article][PubMed]
    [Google Scholar]
  48. Smith T. J., Morrison L. A., Leib D. A. 2002; Pathogenesis of herpes simplex virus type 2 virion host shutoff (vhs) mutants. J Virol 76:2054–2061 [View Article][PubMed]
    [Google Scholar]
  49. Song B., Yeh K. C., Liu J., Knipe D. M. 2001; Herpes simplex virus gene products required for viral inhibition of expression of G1-phase functions. Virology 290:320–328 [View Article][PubMed]
    [Google Scholar]
  50. Suzutani T., Nagamine M., Shibaki T., Ogasawara M., Yoshida I., Daikoku T., Nishiyama Y., Azuma M. 2000; The role of the UL41 gene of herpes simplex virus type 1 in evasion of non-specific host defence mechanisms during primary infection. J Gen Virol 81:1763–1771[PubMed]
    [Google Scholar]
  51. Svensson A., Bellner L., Magnusson M., Eriksson K. 2007; Role of IFN-α/β signaling in the prevention of genital herpes virus type 2 infection. J Reprod Immunol 74:114–123 [View Article][PubMed]
    [Google Scholar]
  52. Taddeo B., Esclatine A., Zhang W., Roizman B. 2003; The stress-inducible immediate-early responsive gene IEX-1 is activated in cells infected with herpes simplex virus 1, but several viral mechanisms, including 3′ degradation of its RNA, preclude expression of the gene. J Virol 77:6178–6187 [View Article][PubMed]
    [Google Scholar]
  53. Taddeo B., Zhang W., Roizman B. 2006; The U(L)41 protein of herpes simplex virus 1 degrades RNA by endonucleolytic cleavage in absence of other cellular or viral proteins. Proc Natl Acad Sci U S A 103:2827–2832 [View Article][PubMed]
    [Google Scholar]
  54. Takeuchi O., Akira S. 2007; Recognition of viruses by innate immunity. Immunol Rev 220:214–224 [View Article][PubMed]
    [Google Scholar]
  55. Thompson A. J., Locarnini S. A. 2007; Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response. Immunol Cell Biol 85:435–445 [View Article][PubMed]
    [Google Scholar]
  56. Tigges M. A., Leng S., Johnson D. C., Burke R. L. 1996; Human herpes simplex virus (HSV)-specific CD8+ CTL clones recognize HSV-2-infected fibroblasts after treatment with IFN-γ or when virion host shutoff functions are disabled. J Immunol 156:3901–3910[PubMed]
    [Google Scholar]
  57. Weaver B. K., Kumar K. P., Reich N. C. 1998; Interferon regulatory factor 3 and CREB-binding protein/p300 are subunits of double-stranded RNA-activated transcription factor DRAF1. Mol Cell Biol 18:1359–1368[PubMed]
    [Google Scholar]
  58. Yao X. D., Fernandez S., Kelly M. M., Kaushic C., Rosenthal K. L. 2007; Expression of Toll-like receptors in murine vaginal epithelium is affected by the estrous cycle and stromal cells. J Reprod Immunol 75:106–119 [View Article][PubMed]
    [Google Scholar]
  59. Zhang Y., Jiang Y., Geiser V., Zhou J., Jones C. 2006; Bovine herpesvirus 1 immediate-early protein (bICP0) interacts with the histone acetyltransferase p300, which stimulates productive infection and gC promoter activity. J Gen Virol 87:1843–1851 [View Article][PubMed]
    [Google Scholar]
  60. Zhang S. Y., Jouanguy E., Ugolini S., Smahi A., Elain G., Romero P., Segal D., Sancho-Shimizu V., Lorenzo L. et al. 2007; TLR3 deficiency in patients with herpes simplex encephalitis. Science 317:1522–1527 [View Article][PubMed]
    [Google Scholar]
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