1887

Abstract

Inactivated orf virus (ORFV, parapoxvirus ovis) induces antiviral activity in animal models of acute and chronic viral infections and exerts strong effects on human immune cells. ORFV activates antigen presenting cells (APC) via CD14 and, probably, Toll-like receptor signalling, and triggers the release of IFN-γ that has been identified as the key mediator of the antiviral activity. After delineating virus proteins as being the most likely active constituent, we aimed to characterize the ORFV proteins responsible for the therapeutic effect. By using a vaccinia virus/ORFV expression library we identified several multi-gene DNA fragments with strong immunomodulatory activity. Together these fragments contain 27 ORFs. The encoded proteins are related to virion structure and transcription but are otherwise unrelated. Two proteins were separately expressed and purified, and demonstrated immunostimulatory activity. Gene expression profiles induced by ORFV and the identified fragments were investigated by microarray analysis. Interestingly, all active fragments induced a similar gene-expression pattern, differing only in quantitative aspects. Obviously, several proteins of ORFV activate similar cellular pathways, modulating APC to generate a strong T-helper 1-dominated immune response. This was balanced by additional induction of immune dampening mechanisms, suggesting regulatory differences compared to single cytokine therapies. We conclude that ORFV may have the potential to enrich the armamentarium of antiviral therapies.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.028894-0
2011-07-01
2019-10-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/7/1571.html?itemId=/content/journal/jgv/10.1099/vir.0.028894-0&mimeType=html&fmt=ahah

References

  1. Alpdogan O. , van den Brink M. R. . ( 2005; ). IL-7 and IL-15: therapeutic cytokines for immunodeficiency. . Trends Immunol 26:, 56–64. [CrossRef].[PubMed].
    [Google Scholar]
  2. Annes J. P. , Munger J. S. , Rifkin D. B. . ( 2003; ). Making sense of latent TGFβ activation. . J Cell Sci 116:, 217–224. [CrossRef].[PubMed].
    [Google Scholar]
  3. Ansel K. M. , Harris R. B. , Cyster J. G. . ( 2002; ). CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. . Immunity 16:, 67–76. [CrossRef].[PubMed].
    [Google Scholar]
  4. Ben-Baruch A. , Grimm M. , Bengali K. , Evans G. A. , Chertov O. , Wang J. M. , Howard O. M. , Mukaida N. , Matsushima K. , Oppenheim J. J. . ( 1997; ). The differential ability of IL-8 and neutrophil-activating peptide-2 to induce attenuation of chemotaxis is mediated by their divergent capabilities to phosphorylate CXCR2 (IL-8 receptor B). . J Immunol 158:, 5927–5933.[PubMed].
    [Google Scholar]
  5. Culley F. J. , Pennycook A. M. , Tregoning J. S. , Dodd J. S. , Walzl G. , Wells T. N. , Hussell T. , Openshaw P. J. . ( 2006; ). Role of CCL5 (RANTES) in viral lung disease. . J Virol 80:, 8151–8157. [CrossRef].[PubMed].
    [Google Scholar]
  6. Dillon S. R. , Gross J. A. , Ansell S. M. , Novak A. J. . ( 2006; ). An APRIL to remember: novel TNF ligands as therapeutic targets. . Nat Rev Drug Discov 5:, 235–246. [CrossRef].[PubMed].
    [Google Scholar]
  7. Elsbach P. , Weiss J. . ( 1993; ). The bactericidal/permeability-increasing protein (BPI), a potent element in host-defense against gram-negative bacteria and lipopolysaccharide. . Immunobiology 187:, 417–429.[PubMed].[CrossRef]
    [Google Scholar]
  8. Fothergill T. , McMillan N. A. . ( 2006; ). Papillomavirus virus-like particles activate the PI3-kinase pathway via α-6 β-4 integrin upon binding. . Virology 352:, 319–328. [CrossRef].[PubMed].
    [Google Scholar]
  9. Friebe A. , Siegling A. , Friederichs S. , Volk H. D. , Weber O. . ( 2004; ). Immunomodulatory effects of inactivated parapoxvirus ovis (ORF virus) on human peripheral immune cells: induction of cytokine secretion in monocytes and . Th1 -like cells. . J Virol 78:, 9400–9411. [CrossRef].[PubMed].
    [Google Scholar]
  10. Fukao T. , Koyasu S. . ( 2003; ). PI3K and negative regulation of TLR signaling. . Trends Immunol 24:, 358–363. [CrossRef].[PubMed].
    [Google Scholar]
  11. Glass W. G. , Rosenberg H. F. , Murphy P. M. . ( 2003; ). Chemokine regulation of inflammation during acute viral infection. . Curr Opin Allergy Clin Immunol 3:, 467–473. [CrossRef].[PubMed].
    [Google Scholar]
  12. Gómez C. E. , Esteban M. . ( 2001; ). Recombinant proteins produced by vaccinia virus vectors can be incorporated within the virion (IMV form) into different compartments. . Arch Virol 146:, 875–892. [CrossRef].[PubMed].
    [Google Scholar]
  13. Groseil C. , Guerin P. , Adamowicz P. . ( 1995; ). Evaluation by polymerase chain reaction on the effect of β-propiolactone and binary ethyleneimine on DNA. . Biologicals 23:, 213–220. [CrossRef].[PubMed].
    [Google Scholar]
  14. Haig D. M. , Thomson J. , McInnes C. , McCaughan C. , Imlach W. , Mercer A. , Fleming S. . ( 2002; ). Orf virus immuno-modulation and the host immune response. . Vet Immunol Immunopathol 87:, 395–399. [CrossRef].[PubMed].
    [Google Scholar]
  15. Harper J. M. M. , Parsonage M. T. , Pelham H. R. B. , Darby G. . ( 1978; ). Heat inactivation of vaccinia virus particle-associated functions: properties of heated particles in vivo and in vitro. . J Virol 26:, 646–659.[PubMed].
    [Google Scholar]
  16. Johnston J. B. , Barrett J. W. , Nazarian S. H. , Goodwin M. , Ricciuto D. , Wang G. , McFadden G. . ( 2005; ). A poxvirus-encoded pyrin domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection. . Immunity 23:, 587–598. [CrossRef].[PubMed].
    [Google Scholar]
  17. Krieg A. M. . ( 2002; ). CpG motifs in bacterial DNA and their immune effects. . Annu Rev Immunol 20:, 709–760. [CrossRef].[PubMed].
    [Google Scholar]
  18. Kumar D. , Hosse J. , von Toerne C. , Noessner E. , Nelson P. J. . ( 2009; ). JNK MAPK pathway regulates constitutive transcription of CCL5 by human NK cells through SP1. . J Immunol 182:, 1011–1020.[PubMed].[CrossRef]
    [Google Scholar]
  19. Mariathasan S. , Newton K. , Monack D. M. , Vucic D. , French D. M. , Lee W. P. , Roose-Girma M. , Erickson S. , Dixit V. M. . ( 2004; ). Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. . Nature 430:, 213–218. [CrossRef].[PubMed].
    [Google Scholar]
  20. Marteau F. , Gonzalez N. S. , Communi D. , Goldman M. , Boeynaems J. M. , Communi D. . ( 2005; ). Thrombospondin-1 and indoleamine 2,3-dioxygenase are major targets of extracellular ATP in human dendritic cells. . Blood 106:, 3860–3866. [CrossRef].[PubMed].
    [Google Scholar]
  21. Masli S. , Turpie B. , Streilein J. W. . ( 2006; ). Thrombospondin orchestrates the tolerance-promoting properties of TGFβ-treated antigen-presenting cells. . Int Immunol 18:, 689–699. [CrossRef].[PubMed].
    [Google Scholar]
  22. Mastroianni C. M. , d'Ettorre G. , Forcina G. , Vullo V. . ( 2004; ). Teaching tired T cells to fight HIV: time to test IL-15 for immunotherapy?. Trends Immunol 25:, 121–125. [CrossRef].[PubMed].
    [Google Scholar]
  23. Mercer A. A. , Yirrell D. L. , Whelan E. M. , Nettleton P. F. , Pow I. , Gilray J. A. , Reid H. W. , Robinson A. J. . ( 1997; ). A novel strategy for determining protective antigens of the parapoxvirus, orf virus. . Virology 229:, 193–200. [CrossRef].[PubMed].
    [Google Scholar]
  24. Mercer A. A. , Ueda N. , Friederichs S. M. , Hofmann K. , Fraser K. M. , Bateman T. , Fleming S. B. . ( 2006; ). Comparative analysis of genome sequences of three isolates of Orf virus reveals unexpected sequence variation. . Virus Res 116:, 146–158. [CrossRef].[PubMed].
    [Google Scholar]
  25. Ng L. G. , Mackay C. R. , Mackay F. . ( 2005; ). The BAFF/APRIL system: life beyond B lymphocytes. . Mol Immunol 42:, 763–772. [CrossRef].[PubMed].
    [Google Scholar]
  26. Penna G. , Vulcano M. , Sozzani S. , Adorini L. . ( 2002; ). Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells. . Hum Immunol 63:, 1164–1171. [CrossRef].[PubMed].
    [Google Scholar]
  27. Perez O. D. , Kinoshita S. , Hitoshi Y. , Payan D. G. , Kitamura T. , Nolan G. P. , Lorens J. B. . ( 2002; ). Activation of the PKB/AKT pathway by ICAM-2. . Immunity 16:, 51–65. [CrossRef].[PubMed].
    [Google Scholar]
  28. Resch W. , Hixson K. K. , Moore R. J. , Lipton M. S. , Moss B. . ( 2007; ). Protein composition of the vaccinia virus mature virion. . Virology 358:, 233–247. [CrossRef].[PubMed].
    [Google Scholar]
  29. Rodriguez J. F. , Paez E. , Esteban M. . ( 1987; ). A 14,000-Mr envelope protein of vaccinia virus is involved in cell fusion and forms covalently linked trimers. . J Virol 61:, 395–404.[PubMed].
    [Google Scholar]
  30. Schramm C. , Huber S. , Protschka M. , Czochra P. , Burg J. , Schmitt E. , Lohse A. W. , Galle P. R. , Blessing M. . ( 2004; ). TGFβ regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo. . Int Immunol 16:, 1241–1249. [CrossRef].[PubMed].
    [Google Scholar]
  31. Trifilo M. J. , Lane T. E. . ( 2004; ). The CC chemokine ligand 3 regulates CD11c+CD11b+CD8α dendritic cell maturation and activation following viral infection of the central nervous system: implications for a role in T cell activation. . Virology 327:, 8–15. [CrossRef].[PubMed].
    [Google Scholar]
  32. Wang S. , Miura M. , Jung Y. K. , Zhu H. , Li E. , Yuan J. . ( 1998; ). Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. . Cell 92:, 501–509. [CrossRef].[PubMed].
    [Google Scholar]
  33. Weber O. , Siegling A. , Friebe A. , Limmer A. , Schlapp T. , Knolle P. , Mercer A. , Schaller H. , Volk H. D. . ( 2003; ). Inactivated parapoxvirus ovis (Orf virus) has antiviral activity against hepatitis B virus and herpes simplex virus. . J Gen Virol 84:, 1843–1852. [CrossRef].[PubMed].
    [Google Scholar]
  34. Wittek R. , Kuenzle C. C. , Wyler R. . ( 1979; ). High C+G content in parapoxvirus DNA. . J Gen Virol 43:, 231–234. [CrossRef].[PubMed].
    [Google Scholar]
  35. Zhai Y. , Qiao B. , Shen X. D. , Gao F. , Busuttil R. W. , Cheng G. , Platt J. L. , Volk H. D. , Kupiec-Weglinski J. W. . ( 2008; ). Evidence for the pivotal role of endogenous toll-like receptor 4 ligands in liver ischemia and reperfusion injury. . Transplantation 85:, 1016–1022. [CrossRef].[PubMed].
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.028894-0
Loading
/content/journal/jgv/10.1099/vir.0.028894-0
Loading

Data & Media loading...

Supplements

vol. , part 6, pp. 1571–1584

DNA isolation, proteinase K treatment, analysis of ORFs on active ORFV NZ2 inserts, protein expression in baculovirus, performance of microarray experiments and flow cytometric analysis. Function of gene products significantly suppressed or induced by ORFV or the active fragments. Comparison of IFN- and TNF- induction by ORFV NZ2 and the in vitro active recombinants. Western Blot showing expression of ORFV ORF 103 protein after infection of 9 cells with recombinant baculovirus. Flow cytometric characterization of peritoneal cells used for microarray analysis.

[ Single PDF file] (353 kB)



PDF

Most Cited This Month

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