Inhibition of Translation Initiation by Protein 169: A Vaccinia Virus Strategy to Suppress Innate and Adaptive Immunity and Alter Virus Virulence


Long after smallpox was eradicated by vaccination with vaccinia virus, the study of this virus continues to reveal novel aspects of the interactions between a virus and the host in which it replicates. In this work we investigated the function of a previously uncharacterized VACV protein, called 169. The results show that protein 169 inhibits the synthesis of host proteins in cells and thereby provides a broad inhibition of the host innate immune response to infection. Unlike several other virus inhibitors of host protein synthesis, protein 169 acts by inhibiting the initiation of protein synthesis by both cap-dependent and cap-independent pathways. Also unlike several other virus protein synthesis inhibitors, the loss of protein 169 does not affect virus replication or spread, but the virus virulence was increased. This more severe infection is, however, cleared more rapidly and results in a stronger immunological memory response that is mediated by T-cells and provides better protection against re-infection. This work illustrates how shutting down host protein synthesis can be a strategy to block the host immune response to infection rather than a means to manufacture more virus particles.


Vyšlo v časopise: Inhibition of Translation Initiation by Protein 169: A Vaccinia Virus Strategy to Suppress Innate and Adaptive Immunity and Alter Virus Virulence. PLoS Pathog 11(9): e32767. doi:10.1371/journal.ppat.1005151
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1005151

Souhrn

Long after smallpox was eradicated by vaccination with vaccinia virus, the study of this virus continues to reveal novel aspects of the interactions between a virus and the host in which it replicates. In this work we investigated the function of a previously uncharacterized VACV protein, called 169. The results show that protein 169 inhibits the synthesis of host proteins in cells and thereby provides a broad inhibition of the host innate immune response to infection. Unlike several other virus inhibitors of host protein synthesis, protein 169 acts by inhibiting the initiation of protein synthesis by both cap-dependent and cap-independent pathways. Also unlike several other virus protein synthesis inhibitors, the loss of protein 169 does not affect virus replication or spread, but the virus virulence was increased. This more severe infection is, however, cleared more rapidly and results in a stronger immunological memory response that is mediated by T-cells and provides better protection against re-infection. This work illustrates how shutting down host protein synthesis can be a strategy to block the host immune response to infection rather than a means to manufacture more virus particles.


Zdroje

1. Fenner F, Anderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization; 1988.

2. Broyles SS. Vaccinia virus transcription. J Gen Virol 2003;84(9):2293–303. doi: 10.1099/vir.0.18942–0

3. Moss B. Poxviridae: the viruses and their replication. In: Knipe DM, Lamb RA, Straus SE, Howley PM, Malcom MA, Roizman B, editors. Fields in Virology. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 2905–46.

4. Mazzon M, Castro C, Roberts LD, Griffin JL, Smith GL. A role for vaccinia virus protein C16 in reprogramming cellular energy metabolism. J Gen Virol 2015;96(Pt 2):395–407. doi: 10.1099/vir.0.069591–0 25351724

5. Mazzon M, Peters NE, Loenarz C, Krysztofinska EM, Ember SWJ, Ferguson BJ, et al. A mechanism for induction of a hypoxic response by vaccinia virus. Proc Natl Acad Sci U S A 2013;110(30):12444–9. doi: 10.1073/pnas.1302140110 PMC3725076.

6. Fontaine KA, Camarda R, Lagunoff M. Vaccinia virus requires glutamine but not glucose for efficient replication. J Virol 2014;88(8):4366–74. doi: 10.1128/JVI.03134-13 24501408

7. Greseth MD, Traktman P. De novo fatty acid biosynthesis contributes significantly to establishment of a bioenergetically favorable environment for vaccinia virus infection. PLoS Pathog 2014;10(3):e1004021. doi: 10.1371/journal.ppat.1004021 PMC3961357.

8. Smith GL, Benfield CTO, Maluquer de Motes C, Mazzon M, Ember SWJ, Ferguson BJ, et al. Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity. J Gen Virol 2013;94(Pt 11):2367–92. doi: 10.1099/vir.0.055921–0 23999164

9. Stack J, Haga IR, Schröder M, Bartlett NW, Maloney G, Reading PC, et al. Vaccinia virus protein A46R targets multiple Toll-like–interleukin-1 receptor adaptors and contributes to virulence. J Exp Med 2005;201(6):1007–18. doi: 10.1084/jem.20041442 PMC2213104.

10. DiPerna G, Stack J, Bowie AG, Boyd A, Kotwal G, Zhang Z, et al. Poxvirus protein N1L targets the I-κB kinase complex, inhibits signaling to NF-κB by the tumor necrosis factor superfamily of receptors, and inhibits NF-κB and IRF3 signaling by Toll-like receptors. J Biol Chem 2004;279(35):36570–8. doi: 10.1074/jbc.M400567200 15215253

11. Myskiw C, Arsenio J, van Bruggen R, Deschambault Y, Cao J. Vaccinia virus E3 suppresses expression of diverse cytokines through inhibition of the PKR, NF-κB, and IRF3 pathways. J Virol 2009;83(13):6757–68. doi: 10.1128/JVI.02570-08 19369349

12. Ember SWJ, Ren H, Ferguson BJ, Smith GL. Vaccinia virus protein C4 inhibits NF-κB activation and promotes virus virulence. J Gen Virol 2012;93(Pt 10):2098–108. doi: 10.1099/vir.0.045070–0 22791606

13. Bowie A, Kiss-Toth E, Symons JA, Smith GL, Dower SK, O'Neill LAJ. A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling. Proc Natl Acad Sci U S A 2000;97(18):10162–7. PMC27775.

14. Schröder M, Baran M, Bowie AG. Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKε-mediated IRF activation. EMBO J 2008;27(15):2147–57. doi: 10.1038/emboj.2008.143 18636090

15. Chen RAJ, Ryzhakov G, Cooray S, Randow F, Smith GL. Inhibition of IκB kinase by vaccinia virus virulence factor B14. PLoS Pathog 2008;4(2):e22. doi: 10.1371/journal.ppat.0040022 18266467

16. Shisler JL, Jin X-L. The vaccinia virus K1L gene product inhibits host NF-κB activation by preventing IκBα degradation. J Virol 2004;78(7):3553–60. doi: 10.1128/JVI.78.7.3553–3560.2004 15016878

17. Mansur DS, Maluquer de Motes C, Unterholzner L, Sumner RP, Ferguson BJ, Ren H, et al. Poxvirus targeting of E3 ligase β-TrCP by molecular mimicry: a mechanism to inhibit NF-κB activation and promote immune evasion and virulence. PLoS Pathog 2013;9(2):e1003183. doi: 10.1371/journal.ppat.1003183 23468625

18. Gedey R, Jin X-L, Hinthong O, Shisler JL. Poxviral regulation of the host NF-κB response: the vaccinia virus M2L protein inhibits induction of NF-κB activation via an ERK2 pathway in virus-infected human embryonic kidney cells. J Virol 2006;80(17):8676–85. doi: 10.1128/JVI.00935-06 16912315

19. Sumner RP, Maluquer de Motes C, Veyer DL, Smith GL. Vaccinia virus inhibits NF-κB-dependent gene expression downstream of p65 translocation. J Virol 2014;88(6):3092–102. doi: 10.1128/JVI.02627-13 24371075

20. Harford CG, Hamlin A, Rieders E. Electron microscopic autoradiography of DNA synthesis in cells infected with vaccinia virus. Exp Cell Res 1966;42(1):50–7. doi: 10.1016/0014-4827(66)90318-1 5929573

21. Katsafanas GC, Moss B. Linkage of transcription and translation within cytoplasmic poxvirus DNA factories provides a mechanism to coordinate viral and usurp host functions. Cell Host Microbe 2007;2(4):221–8. doi: 10.1016/j.chom.2007.08.005 PMC2084088.

22. Cooper JA, Moss B. In Vitro translation of immediate early, early, and late classes of RNA from vaccinia virus-infected cells. Virology 1979;96(2):368–80. doi: 10.1016/0042-6822(79)90095-3 462811

23. Rice AP, Roberts BE. Vaccinia virus induces cellular mRNA degradation. J Virol 1983;47(3):529–39. PMC255294.

24. Pedley S, Cooper RJ. The inhibition of HeLa cell RNA synthesis following infection with vaccinia Virus. J Gen Virol 1984;65(10):1687–97. doi: 10.1099/0022-1317-65-10-1687

25. Shors T, Keck JG, Moss B. Down regulation of gene expression by the vaccinia virus D10 protein. J Virol 1999;73(1):791–6. PMC103891.

26. Parrish S, Moss B. Characterization of a vaccinia virus mutant with a deletion of the D10R gene encoding a putative negative regulator of gene expression. J Virol 2006;80(2):553–61. doi: 10.1128/JVI.80.2.553–561.2006 PMC1346865.

27. Walsh D, Arias C, Perez C, Halladin D, Escandon M, Ueda T, et al. Eukaryotic translation initiation factor 4F architectural alterations accompany translation initiation factor redistribution in poxvirus-infected cells. Mol Cell Biol 2008;28(8):2648–58. doi: 10.1128/MCB.01631-07 18250159

28. Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 2009;136(4):731–45. doi: 10.1016/j.cell.2009.01.042 PMC3610329.

29. Martin SA, Moss B. Modification of RNA by mRNA guanylyltransferase and mRNA (guanine-7-)methyltransferase from vaccinia virions. J Biol Chem 1975;250(24):9330–5. 1194287

30. Barbosa E, Moss B. mRNA(nucleoside-2'-)-methyltransferase from vaccinia virus. Characteristics and substrate specificity. J Biol Chem 1978;253(21):7698–702. 701282

31. Zaborowska I, Kellner K, Henry M, Meleady P, Walsh D. Recruitment of host translation initiation factor eIF4G by the Vaccinia Virus ssDNA-binding protein I3. Virology 2012;425(1):11–22. doi: 10.1016/j.virol.2011.12.022 22280895

32. Parrish S, Moss B. Characterization of a second vaccinia virus mRNA-decapping enzyme conserved in poxviruses. J Virol 2007;81(23):12973–8. doi: 10.1128/JVI.01668-07 PMC2169080.

33. Parrish S, Resch W, Moss B. Vaccinia virus D10 protein has mRNA decapping activity, providing a mechanism for control of host and viral gene expression. Proc Natl Acad Sci U S A 2007;104(7):2139–44. doi: 10.1073/pnas.0611685104 17283339

34. Liu S-W, Wyatt LS, Orandle MS, Minai M, Moss B. The D10 decapping enzyme of vaccinia virus contributes to decay of cellular and viral mRNAs and to virulence in mice. J Virol 2014;88(1):202–11. doi: 10.1128/JVI.02426-13 PMC3911708.

35. Liu S-W, Katsafanas George C, Liu R, Wyatt Linda S, Moss B. Poxvirus decapping enzymes enhance virulence by preventing the accumulation of dsRNA and the induction of innate antiviral responses. Cell Host Microbe 2015;17(3):320–31. doi: 10.1016/j.chom.2015.02.002 25766293

36. Burgess Hannah M, Mohr I. Cellular 5′-3′ mRNA exonuclease Xrn1 controls double-stranded RNA accumulation and anti-viral responses. Cell Host Microbe 2015;17(3):332–44. doi: 10.1016/j.chom.2015.02.003 25766294

37. Parkinson JE, Smith GL. Vaccinia virus gene A36R encodes a Mr 43–50 K protein on the surface of extracellular enveloped virus. Virology 1994;204(1):376–90. doi: 10.1006/viro.1994.1542 8091668

38. Fahy AS, Clark RH, Glyde EF, Smith GL. Vaccinia virus protein C16 acts intracellularly to modulate the host response and promote virulence. J Gen Virol 2008;89(10):2377–87. doi: 10.1099/vir.0.2008/004895-0

39. Niles EG, Seto J. Vaccinia virus gene D8 encodes a virion transmembrane protein. J Virol 1988;62(10):3772–8. 3418784

40. Falkner FG, Moss B. Escherichia coli gpt gene provides dominant selection for vaccinia virus open reading frame expression vectors. J Virol 1988;62(6):1849–54. 3130492

41. Alcamí A, Symons JA, Smith GL. The vaccinia virus soluble alpha/beta interferon (IFN) receptor binds to the cell surface and protects cells from the antiviral effects of IFN. J Virol 2000;74(23):11230–9. doi: 10.1128/JVI.74.23.11230–11239.2000 11070021

42. Symons JA, Alcamí A, Smith GL. Vaccinia virus encodes a soluble type I interferon receptor of novel structure and broad species soecificity. Cell 1995;81(4):551–60. doi: 10.1016/0092-8674(95)90076-4 7758109

43. Moore JB, Smith GL. Steroid hormone synthesis by a vaccinia enzyme: a new type of virus virulence factor. EMBO J 1992;11(5):1973–80. PMC556657.

44. Reading PC, Moore JB, Smith GL. Steroid hormone synthesis by vaccinia virus suppresses the inflammatory response to infection. J Exp Med 2003;197(10):1269–78. doi: 10.1084/jem.20022201 PMC2193778.

45. Unterholzner L, Sumner RP, Baran M, Ren H, Mansur DS, Bourke NM, et al. Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7. PLoS Pathog 2011;7(9):e1002247. doi: 10.1371/journal.ppat.1002247 21931555

46. Didcock L, Young DF, Goodbourn S, Randall RE. The V protein of simian virus 5 inhibits interferon signalling by targeting STAT1 for proteasome-mediated degradation. J Virol 1999;73(12):9928–33. 10559305

47. Maluquer de Motes C, Cooray S, Ren H, Almeida GMF, McGourty K, Bahar MW, et al. Inhibition of apoptosis and NF-κB activation by vaccinia protein N1 occur via distinct binding surfaces and make different contributions to virulence. PLoS Pathog 2011;7(12):e1002430. doi: 10.1371/journal.ppat.1002430 22194685

48. Cooray S, Bahar MW, Abrescia NGA, McVey CE, Bartlett NW, Chen RAJ, et al. Functional and structural studies of the vaccinia virus virulence factor N1 reveal a Bcl-2-like anti-apoptotic protein. J Gen Virol 2007;88(6):1656–66. doi: 10.1099/vir.0.82772–0

49. Schmidt EK, Clavarino G, Ceppi M, Pierre P. SUnSET, a nonradioactive method to monitor protein synthesis. Nat Meth 2009;6(4):275–7. doi: 10.1038/nmeth.1314

50. Ferguson BJ, Benfield CTO, Ren H, Lee VH, Frazer GL, Strnadova P, et al. Vaccinia virus protein N2 is a nuclear IRF3 inhibitor that promotes virulence. J Gen Virol 2013;94(Pt 9):2070–81. doi: 10.1099/vir.0.054114–0 23761407

51. Pestova TV, Hellen CUT. Translation elongation after assembly of ribosomes on the Cricket paralysis virus internal ribosomal entry site without initiation factors or initiator tRNA. Gene Dev 2003;17(2):181–6. doi: 10.1101/gad.1040803 PMC195975.

52. Williamson JD, Reith RW, Jeffrey LJ, Arrand JR, Mackett M. Biological characterization of recombinant vaccinia viruses in mice infected by the respiratory route. J Gen Virol 1990;71(11):2761–7. doi: 10.1099/0022-1317-71-11-2761

53. Alcami A, Smith GL. A soluble receptor for interleukin-1β encoded by vaccinia virus: A novel mechanism of virus modulation of the host response to infection. Cell 1992;71(1):153–67. doi: 10.1016/0092-8674(92)90274-G 1394428

54. Tscharke DC, Smith GL. A model for vaccinia virus pathogenesis and immunity based on intradermal injection of mouse ear pinnae. J Gen Virol 1999;80(10):2751–5.

55. Tscharke DC, Reading PC, Smith GL. Dermal infection with vaccinia virus reveals roles for virus proteins not seen using other inoculation routes. J Gen Virol 2002;83(8):1977–86.

56. Ng A, Tscharke DC, Reading PC, Smith GL. The vaccinia virus A41L protein is a soluble 30 kDa glycoprotein that affects virus virulence. J Gen Virol 2001;82(9):2095–105.

57. Clark RH, Kenyon JC, Bartlett NW, Tscharke DC, Smith GL. Deletion of gene A41L enhances vaccinia virus immunogenicity and vaccine efficacy. J Gen Virol 2006;87(1):29–38. doi: 10.1099/vir.0.81417–0

58. Bahar MW, Kenyon JC, Putz MM, Abrescia NGA, Pease JE, Wise EL, et al. Structure and function of A41, a vaccinia virus chemokine binding protein. PLoS Pathog 2008;4(1):e5. doi: 10.1371/journal.ppat.0040005 PMC2211551.

59. García-Arriaza J, Arnáez P, Gómez CE, Sorzano CÓS, Esteban M. Improving adaptive and memory immune responses of an HIV/AIDS vaccine candidate MVA-B by deletion of vaccinia virus genes (C6L and K7R) blocking interferon signaling pathways. PLoS ONE 2013;8(6):e66894. doi: 10.1371/journal.pone.0066894 PMC3694958.

60. Sumner RP, Ren H, Smith GL. Deletion of immunomodulator C6 from vaccinia virus strain Western Reserve enhances virus immunogenicity and vaccine efficacy. J Gen Virol 2013;94(Pt 5):1121–6. doi: 10.1099/vir.0.049700–0 PMC3709586.

61. Bartlett N, Symons JA, Tscharke DC, Smith GL. The vaccinia virus N1L protein is an intracellular homodimer that promotes virulence. J Gen Virol 2002;83(8):1965–76.

62. Ren H, Ferguson BJ, de Motes CM, Sumner RP, Harman LER, Smith GL. Enhancement of CD8+ T-cell memory by removal of a vaccinia virus nuclear factor-κB inhibitor. Immunology 2015;145(1):34–49. doi: 10.1111/imm.12422 25382035

63. Willcocks MM, Carter MJ, Roberts LO. Cleavage of eukaryotic initiation factor eIF4G and inhibition of host-cell protein synthesis during feline calicivirus infection. J Gen Virol 2004;85(5):1125–30. doi: 10.1099/vir.0.19564–0

64. Ventoso I, Blanco R, Perales C, Carrasco L. HIV-1 protease cleaves eukaryotic initiation factor 4G and inhibits cap-dependent translation. Proc Natl Acad Sci U S A 2001;98(23):12966–71. doi: 10.2307/3057024 11606767

65. Etchison D, Milburn SC, Edery I, Sonenberg N, Hershey JW. Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex. J Biol Chem 1982;257(24):14806–10. 6294080

66. Kuyumcu-Martinez M, Belliot G, Sosnovtsev SV, Chang K-O, Green KY, Lloyd RE. Calicivirus 3C-like proteinase inhibits cellular translation by cleavage of poly(A)-binding protein. J Virol 2004;78(15):8172–82. doi: 10.1128/JVI.78.15.8172–8182.2004 15254188

67. Kuyumcu-Martinez NM, Joachims M, Lloyd RE. Efficient cleavage of ribosome-associated poly(A)-binding protein by enterovirus 3C protease. J Virol 2002;76(5):2062–74. doi: 10.1128/jvi.76.5.2062–2074.2002 PMC135927.

68. Connor JH, Lyles DS. Vesicular stomatitis virus infection alters the eIF4F translation initiation complex and causes dephosphorylation of the eIF4E binding protein 4E-BP1. J Virol 2002;76(20):10177–87. doi: 10.1128/JVI.76.20.10177–10187.2002 12239292

69. Feigenblum D, Schneider RJ. Modification of eukaryotic initiation factor 4F during infection by influenza virus. J Virol 1993;67(6):3027–35. PMC237639.

70. Walsh D, Mohr I. Phosphorylation of eIF4E by Mnk-1 enhances HSV-1 translation and replication in quiescent cells. Gene Dev 2004;18(6):660–72. doi: 10.1101/gad.1185304 PMC387241.

71. Walsh D, Mohr I. Assembly of an active translation initiation factor complex by a viral protein. Gene Dev 2006;20(4):461–72. doi: 10.1101/gad.1375006 PMC1369048.

72. Garaigorta U, Chisari FV. Hepatitis C virus blocks interferon effector function by inducing PKR phosphorylation. Cell Host Microbe 2009;6(6):513–22. doi: 10.1016/j.chom.2009.11.004 PMC2905238.

73. Assarsson E, Greenbaum JA, Sundström M, Schaffer L, Hammond JA, Pasquetto V, et al. Kinetic analysis of a complete poxvirus transcriptome reveals an immediate-early class of genes. Proc Natl Acad Sci U S A 2008;105(6):2140–5. doi: 10.1073/pnas.0711573105 18245380

74. Chou W, Ngo T, Gershon PD. An overview of the vaccinia virus infectome: a survey of the proteins of the poxvirus-infected cell. J Virol 2012;86(3):1487–99. doi: 10.1128/JVI.06084-11 22090131

75. Alcamí A, Smith GL. A mechanism for the inhibition of fever by a virus. Proc Natl Acad Sci U S A 1996;93(20):11029–34. PMC38278.

76. Staib C, Kisling S, Erfle V, Sutter G. Inactivation of the viral interleukin 1β receptor improves CD8+ T-cell memory responses elicited upon immunization with modified vaccinia virus Ankara. J Gen Virol 2005;86(7):1997–2006. doi: 10.1099/vir.0.80646–0

77. Ren H, Ferguson BJ, Maluquer de Motes C, Sumner RP, Harman L, Smith GL. Enhancement of CD8+ T-cell memory by removal of a vaccinia virus NF-κB inhibitor. Immunology 2014. doi: 10.1111/imm.12422

78. Martin TE, Hartwell LH. Resistance of active yeast ribosomes to dissociation by KCl. J Biol Chem 1970;245(6):1504–6. 5442831

79. Groppo R, Palmenberg AC. Cardiovirus 2A protein associates with 40S but not 80S ribosome subunits during infection. J Virol 2007;81(23):13067–74. doi: 10.1128/JVI.00185-07 PMC2169094.

80. Chen RAJ, Jacobs N, Smith GL. Vaccinia virus strain Western Reserve protein B14 is an intracellular virulence factor. J Gen Virol 2006;87(6):1451–8. doi: 10.1099/vir.0.81736–0

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