Poxviral TNFRs: Properties and Role in Viral Pathogenesis

  • Alí Alejo
  • Sergio M. Pontejo
  • Antonio Alcami
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)


Tumor necrosis factor (TNF) is the prototypical member of a large superfamily of structurally related cytokines that are involved in a wide range of activities involved in the regulation of the immune response and developmental processes and that signal mainly through an equally diverse array of receptors included in the TNF receptor superfamily (TNFRSF). TNF has an essential role in the activation of the antiviral immune response, where it acts both directly on virus-infected cells as a cell death-inducing cytokine and indirectly in the activation of the innate and adaptive immune responses against the invading pathogen. Consequently, viruses from different families have devised strategies to evade or modulate these TNF-driven responses. Most strategies involve the expression of virus-encoded intracellular proteins that are able to bind to different proteins of the TNFR signal transduction pathways. Uniquely, poxviruses express secreted TNFR homologues that can bind to soluble TNF, inhibiting its activity by preventing it from binding to the cellular receptors. In the recent years, we have been interested in studying the activity and function of these viral TNFRs (vTNFRs) both in vitro and during infection. We describe recent advances in this field.


Tumor Necrosis Factor Antiviral Immune Response Molluscum Contagiosum Myxoma Virus Main Target Organ 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Alcami A, Khanna A, Paul NL, Smith GL (1999) Vaccinia virus strains Lister, USSR and Evans express soluble and cell-surface tumour necrosis factor receptors. J Gen virol 80(Pt 4):949–959PubMedGoogle Scholar
  2. 2.
    Alejo A, Ruiz-Arguello MB, Ho Y, Smith VP, Saraiva M, Alcami A (2006) A chemokine-binding domain in the tumor necrosis factor receptor from variola (smallpox) virus. Proc Natl Acad Sci USA 103(15):5995–6000CrossRefPubMedGoogle Scholar
  3. 3.
    Alejo A, Saraiva M, Ruiz-Arguello MB, Viejo-Borbolla A, de Marco MF, Salguero FJ, Alcami A (2009) A Method for the generation of ectromelia virus (ECTV) recombinants: in vivo analysis of ECTV vCD30 deletion mutants. PLoS One 4(4), e5175CrossRefPubMedGoogle Scholar
  4. 4.
    Atrasheuskaya AV, Bukin EK, Fredeking TM, Ignatyev GM (2004) Protective effect of exogenous recombinant mouse interferon-gamma and tumour necrosis factor-alpha on ectromelia virus infection in susceptible BALB/c mice. Clin Exp Immunol 136(2), 207–214CrossRefPubMedGoogle Scholar
  5. 5.
    Brunetti CR, Paulose-Murphy M, Singh R, Qin J, Barrett JW, Tardivel A, Schneider P, Essani K, McFadden G (2003) A secreted high-affinity inhibitor of human TNF from Tanapox virus. Proc Natl Acad Sci USA 100(8):4831–4836CrossRefPubMedGoogle Scholar
  6. 6.
    Di Giulio DB, Eckburg PB (2004) Human monkeypox: an emerging zoonosis. Lancet Infect Dis 4(1), 15–25CrossRefPubMedGoogle Scholar
  7. 7.
    Esteban DJ, Buller RM (2005) Ectromelia virus: the causative agent of mousepox. J Gen Virol 86(Pt 10), 2645–2659CrossRefPubMedGoogle Scholar
  8. 8.
    Gileva IP, Nepomnyashchikh TS, Antonets DV, Lebedev LR, Kochneva GV, Grazhdantseva AV, Shchelkunov SN (2006) Properties of the recombinant TNF-binding proteins from variola, monkeypox, and cowpox viruses are different. Biochim Biophys Acta 1764(11):1710–1718PubMedGoogle Scholar
  9. 9.
    Graham SC, Bahar MW, Abrescia NG, Smith GL, Stuart DI, Grimes JM (2007) Structure of CrmE, a virus-encoded tumour necrosis factor receptor. J Mol Biol 372(3), 660–671CrossRefPubMedGoogle Scholar
  10. 10.
    Hu FQ, Smith CA, Pickup DJ (1994) Cowpox virus contains two copies of an early gene encoding a soluble secreted form of the type II TNF receptor. Virology 204(1):343–356CrossRefPubMedGoogle Scholar
  11. 11.
    Loetscher H, Schlaeger EJ, Lahm HW, Pan YC, Lesslauer W, Brockhaus M (1990) Purification and partial amino acid sequence analysis of two distinct tumor necrosis factor receptors from HL60 cells. J Biol Chem 265(33), 20131–20138PubMedGoogle Scholar
  12. 12.
    Loparev VN, Parsons JM, Knight JC, Panus JF, Ray CA, Buller RM, Pickup DJ, Esposito JJ (1998) A third distinct tumor necrosis factor receptor of orthopoxviruses. Proc Natl Acad Sci USA 95(7):3786–3791CrossRefPubMedGoogle Scholar
  13. 13.
    Moss B (2007) Poxviridae: the viruses and their replication. In: Fields BN, Knipe DM, Howley PM (eds) Fields virology, vol. 2. Lippincott Williams & Wilkins, Philadelphia, pp 2905–2946, 2 vols.Google Scholar
  14. 14.
    Palumbo GJ, Buller RM, Glasgow WC (1994) Multigenic evasion of inflammation by poxviruses. J Virol 68(3), 1737–1749PubMedGoogle Scholar
  15. 15.
    Panus JF, Smith CA, Ray CA, Smith TD, Patel DD, Pickup DJ (2002) Cowpox virus encodes a fifth member of the tumor necrosis factor receptor family: a soluble, secreted CD30 homologue. Proc Natl Acad Sci USA 99(12), 8348–8353CrossRefPubMedGoogle Scholar
  16. 16.
    Rahman MM, Jeng D, Singh R, Coughlin J, Essani K, McFadden G (2009) Interaction of human TNF and beta2-microglobulin with Tanapox virus-encoded TNF inhibitor, TPV-2L. Virology 386(2):462–468CrossRefPubMedGoogle Scholar
  17. 17.
    Rahman MM, McFadden G (2006) Modulation of tumor necrosis factor by microbial pathogens. PLoS pathog 2:e4Google Scholar
  18. 18.
    Reading PC, Khanna A, Smith GL (2002) Vaccinia virus CrmE encodes a soluble and cell surface tumor necrosis factor receptor that contributes to virus virulence. Virology 292(2), 285–298CrossRefPubMedGoogle Scholar
  19. 19.
    Rubins KH, Hensley LE, Jahrling PB, Whitney AR, Geisbert TW, Huggins JW, Owen A, Leduc JW, Brown PO, Relman DA (2004) The host response to smallpox: analysis of the gene expression program in peripheral blood cells in a nonhuman primate model. Proc Natl Acad Sci U S A 101(42), 15190–15195CrossRefPubMedGoogle Scholar
  20. 20.
    Ruby J, Bluethmann H, Peschon JJ (1997) Antiviral activity of tumor necrosis factor (TNF) is mediated via p55 and p75 TNF receptors. J Exp Med 186(9), 1591–1596CrossRefPubMedGoogle Scholar
  21. 21.
    Saraiva M, Smith P, Fallon PG, Alcami A (2002) Inhibition of type 1 cytokine-mediated inflammation by a soluble CD30 homologue encoded by ectromelia (mousepox) virus. J Exp Med 196(6), 829–839CrossRefPubMedGoogle Scholar
  22. 22.
    Schall TJ, Lewis M, Koller KJ, Lee A, Rice GC, Wong GH, Gatanaga T, Granger GA, Lentz R, Raab H, et al. (1990) Molecular cloning and expression of a receptor for human tumor necrosis factor. Cell 61(2), 361–370CrossRefPubMedGoogle Scholar
  23. 23.
    Schreiber M, McFadden G (1996) Mutational analysis of the ligand-binding domain of M-T2 protein, the tumor necrosis factor receptor homologue of myxoma virus. J Immunol 157(10), 4486–4495PubMedGoogle Scholar
  24. 24.
    Schreiber M, Rajarathnam K, McFadden G (1996) Myxoma virus T2 protein, a tumor necrosis factor (TNF) receptor homolog, is secreted as a monomer and dimer that each bind rabbit TNFalpha, but the dimer is a more potent TNF inhibitor. J Biol Chem 271(23), 13333–13341CrossRefPubMedGoogle Scholar
  25. 25.
    Schreiber M, Sedger L, McFadden G (1997) Distinct domains of M-T2, the myxoma virus tumor necrosis factor (TNF) receptor homolog, mediate extracellular TNF binding and intracellular apoptosis inhibition. J Virol 71(3):2171–2181PubMedGoogle Scholar
  26. 26.
    Sedger L, McFadden G (1996) M-T2: a poxvirus TNF receptor homologue with dual activities. Immunol Cell Biol 74(6):538–545.CrossRefPubMedGoogle Scholar
  27. 27.
    Smith CA, Davis T, Anderson D, Solam L, Beckmann MP, Jerzy R, Dower SK, Cosman D, Goodwin RG (1990) A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science 248(4958):1019–1023CrossRefPubMedGoogle Scholar
  28. 28.
    Smith CA, Davis T, Wignall JM, Din WS, Farrah T, Upton C, McFadden G, Goodwin RG (1991) T2 open reading frame from the Shope fibroma virus encodes a soluble form of the TNF receptor. Biochem Biophys Res Commun 176(1):335–342CrossRefPubMedGoogle Scholar
  29. 29.
    Smith CA, Hu FQ, Smith TD, Richards CL, Smolak P, Goodwin RG, Pickup DJ (1996) Cowpox virus genome encodes a second soluble homologue of cellular TNF receptors, distinct from CrmB, that binds TNF but not LT alpha. Virology 223(1):132–147CrossRefPubMedGoogle Scholar
  30. 30.
    Upton C, Macen JL, Schreiber M, McFadden G (1991) Myxoma virus expresses a secreted protein with homology to the tumor necrosis factor receptor gene family that contributes to viral virulence. Virology 184(1):370–382CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Alí Alejo
    • 1
  • Sergio M. Pontejo
    • 2
  • Antonio Alcami
    • 3
  1. 1.Centro de Investigación en Sanidad Animal, Instituto Nacional de Investigación y Tecnología Agraria y AlimentariaMadridSpain
  2. 2.Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid)MadridSpain
  3. 3.Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid)MadridSpain

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