Skip to main content
SpringerLink
Log in

Impact on antibody responses of B-cell-restricted transgenic expression of a viral gene inhibiting activation of NF-κB and NFAT

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

In this work, we have assessed the impact in vivo of the evasion gene A238L of African swine fever virus, an inhibitor of both NF-κB- and NFAT-mediated transcription. The A238L gene was selectively expressed in mouse B lymphocytes using the promoter and enhancer sequences of the mouse Ig μ heavy chain. The IgM primary and IgG2b secondary serological responses and the number of splenic germinal centres in response to the TD antigens DNP-keyhole limpet hemocyanin and sheep red blood cells, respectively, were both lower in the transgenic mice, whereas the response to the TI type-1 and type-2 antigens DNP-Ficoll and DNP-LPS, respectively, were normal, except for the increased levels of IgG3 at day 14 in the DNP-LPS-immunized mice. Thus, it appears that neither p65 (NF-κB) nor NFAT is essential for B-cell development but, in a manner that is still unclear, may be relevant for their function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Finlay BB, McFadden G (2006) Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell 124(4):767–782. doi:10.1016/j.cell.2006.01.034

    Article  CAS  PubMed  Google Scholar 

  2. Vischer HF, Vink C, Smit MJ (2006) A viral conspiracy: hijacking the chemokine system through virally encoded pirated chemokine receptors. Curr Top Microbiol Immunol 303:121–154

    CAS  PubMed  Google Scholar 

  3. Loo YM, Gale M (2007) Viral regulation and evasion of the host response. Curr Top Microbiol Immunol 316:295–313

    CAS  PubMed  Google Scholar 

  4. Unterholzner L, Bowie AG (2008) The interplay between viruses and innate immune signaling: recent insights and therapeutic opportunities. Biochem Pharmacol 75(3):589–602. doi:10.1016/j.bcp.2007.07.043

    Article  CAS  PubMed  Google Scholar 

  5. Bonjardim CA, Ferreira PCP, Kroon EG (2009) Interferons: signaling, antiviral and viral evasion. Immunol Lett 122(1):1–11. doi:10.1016/j.imlet.2008.11.002

    Article  CAS  PubMed  Google Scholar 

  6. Jonjić S, Babić M, Polić B, Krmpotić A (2008) Immune evasion of natural killer cells by viruses. Curr Opin Immunol 20(1):30–38. doi:10.1016/j.coi.2007.11.002

    Article  PubMed Central  PubMed  Google Scholar 

  7. Revilla Y, Granja AG (2009) Viral mechanisms involved in the transcriptional CBP/p300 regulation of inflammatory and immune responses. Crit Rev Immunol 29(2):131–154. doi:10.1615/CritRevImmunol.v29.i2.30

    Article  CAS  PubMed  Google Scholar 

  8. Zhou F (2009) Molecular mechanisms of viral immune evasion proteins to inhibit MHC class I antigen processing and presentation. Int Rev Immunol 28(5):376–393. doi:10.1080/08830180903013034

    Article  CAS  PubMed  Google Scholar 

  9. Powell PP, Dixon LK, Parkhouse RM (1996) An IkappaB homolog encoded by African swine fever virus provides a novel mechanism for downregulation of proinflammatory cytokine responses in host macrophages. J Virol 70(12):8527–8533. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC190944/pdf/708527.pdf

  10. Revilla Y, Callejo M, Rodríguez JM, Culebras E, Nogal ML, Salas ML et al (1998) Inhibition of nuclear factor kappaB activation by a virus-encoded IkappaB-like protein. J Biol Chem (Internet) 273(9):5405–5411. doi:10.1074/jbc.273.9.5405

    Article  CAS  Google Scholar 

  11. Miskin JE, Abrams CC, Goatley LC, Dixon LK (1998) A viral mechanism for inhibition of the cellular phosphatase calcineurin (New York, NY). Science 281(5376):562–565. doi:10.1126/science.281.5376.562

    Article  CAS  PubMed  Google Scholar 

  12. Miskin JE, Abrams CC, Dixon LK (2000) African swine fever virus protein A238L interacts with the cellular phosphatase calcineurin via a binding domain similar to that of NFAT. J Virol 74:9412–9420. doi:10.1128/JVI.74.20.9412-9420.2000

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Granja AG, Nogal ML, Hurtado C, Vila V, Carrascosa AL, Salas ML et al (2004) The viral protein A238L inhibits cyclooxygenase-2 expression through a nuclear factor of activated T cell-dependent transactivation pathway. J Biol Chem 279:53736–53746. doi:10.1074/jbc.M406620200

    Article  CAS  PubMed  Google Scholar 

  14. Granja AG, Nogal ML, Hurtado C, Del Aguila C, Carrascosa AL, Salas ML et al (2006) The viral protein A238L inhibits TNF-alpha expression through a CBP/p300 transcriptional coactivators pathway. J Immunol 176:451–462. doi:10.4049/jimmunol.176.1.451

    Article  CAS  PubMed  Google Scholar 

  15. Granja AG, Sabina P, Salas ML, Fresno M, Revilla Y (2006) Regulation of inducible nitric oxide synthase expression by viral A238L-mediated inhibition of p65/RelA acetylation and p300 transactivation. J Virol 80:10487–10496. doi:10.1128/JVI.00862-06

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Granja AG, Perkins ND, Revilla Y (2008) A238L inhibits NF-ATc2, NF-kappa B, and c-Jun activation through a novel mechanism involving protein kinase C-theta-mediated up-regulation of the amino-terminal transactivation domain of p300. J Immunol 180:2429–2442. doi:10.4049/jimmunol.180.4.2429

    Article  CAS  PubMed  Google Scholar 

  17. Granja AG, Sánchez EG, Sabina P, Fresno M, Revilla Y (2009) African swine fever virus blocks the host cell antiviral inflammatory response through a direct inhibition of PKC-theta-mediated p300 transactivation. J Virol 83(2):969–980. doi:10.1128/JVI.01663-08

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Gerritsen ME, Williams AJ, Neish AS, Moore S, Shi Y, Collins T (1997) CREB-binding protein/p300 are transcriptional coactivators of p65. Proc Natil Acad Sci USA 94(7):2927–2932. Available from http://www.pnas.org/content/94/7/2927.full.pdf+html

  19. Perkins ND, Felzien LK, Betts JC, Leung K, Beach DH, Nabel GJ (1997) Regulation of NF-kappa B by cyclin-dependent kinases associated with the p300 coactivator. Science 275:523–527. doi:10.1126/science.275.5299.523

    Article  CAS  PubMed  Google Scholar 

  20. García-Rodríguez C, Rao A (1998) Nuclear factor of activated T cells (NFAT)-dependent transactivation regulated by the coactivators p300/CREB-binding protein (CBP). J Exp Med 187(12):2031–2036. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2212364/pdf/98-0100.pdf

  21. Almeida SCP, de Oliveira VL, Ventura S, Bofill M, Parkhouse RME (2012) Neoplastic transformation of T lymphocytes through transgenic expression of a virus host modification protein. PloS One 7(4):e34140. doi:10.1371/journal.pone.0034140

    Article  PubMed Central  PubMed  Google Scholar 

  22. Jung D, Giallourakis C, Mostoslavsky R, Alt FW (2006) Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol 24:541–570. doi:10.1146/annurev.immunol.23.021704.115830

    Article  CAS  PubMed  Google Scholar 

  23. Matsuda S, Shibasaki F, Takehana K, Mori H, Nishida E, Koyasu S (2000) Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation. EMBO Rep 1(5):428–434. doi:10.1093/embo-reports/kvd090

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Tait SW, Reid EB, Greaves DR, Wileman TE, Powell PP (2000) Mechanism of inactivation of NF-kappa B by a viral homologue of I kappa b alpha. Signal-induced release of i kappa b alpha results in binding of the viral homologue to NF-kappa B. J Biol Chem 275(44):34656–34664. doi:10.1074/jbc.M000320200

    Article  CAS  PubMed  Google Scholar 

  25. Gerondakis S, Grossmann M, Nakamura Y, Pohl T, Grumont R (1999) Genetic approaches in mice to understand Rel/NF-kappaB and IkappaB function: transgenics and knockouts. Oncogene 18(49):6888–6895. Available from http://www.nature.com/onc/journal/v18/n49/pdf/1203236a.pdf

  26. Liou HC, Sha WC, Scott ML, Baltimore D (1994) Sequential induction of NF-kappa B/Rel family proteins during B-cell terminal differentiation. Mol Cell Biol 14(8):5349–5359. doi:10.1128/MCB.14.8.5349

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Doi TS, Takahashi T, Taguchi O, Azuma T, Obata Y (1997) NF-kappa B RelA-deficient lymphocytes: normal development of T cells and B cells, impaired production of IgA and IgG1 and reduced proliferative responses. J Exp Med 185(5):953–961. doi:10.1084/jem.185.5.953

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Alcamo E, Hacohen N, Schulte LC, Rennert PD, Hynes RO, Baltimore D (2002) Requirement for the NF-kappaB family member RelA in the development of secondary lymphoid organs. J Exp Med 195(2):233–244. doi:10.1084/jem.20011885

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Sha WC, Liou HC, Tuomanen EI, Baltimore D (1995) Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 80(2):321–330. doi:10.1016/0092-8674(95)90415-8

    Article  CAS  PubMed  Google Scholar 

  30. Snapper CM, Rosas FR, Zelazowski P, Moorman MA, Kehry MR, Bravo R et al (1996) B cells lacking RelB are defective in proliferative responses, but undergo normal B cell maturation to Ig secretion and Ig class switching. J Exp Med 184(4):1537–41. Available from http://jem.rupress.org/content/184/4/1537.long

  31. Schwarz EM, Krimpenfort P, Berns A, Verma IM (1997) Immunological defects in mice with a targeted disruption in Bcl-3. Genes Dev 11(2):187–197. doi:10.1101/gad.11.2.187

    Article  CAS  PubMed  Google Scholar 

  32. Paxian S, Merkle H, Riemann M, Wilda M, Adler G, Hameister H et al (2002) Abnormal organogenesis of Peyer’s patches in mice deficient for NF-kappaB1, NF-kappaB2, and Bcl-3. Gastroenterology 122(7):1853–1868. doi:10.1053/gast.2002.33651

    Article  CAS  PubMed  Google Scholar 

  33. Crabtree GR, Olson EN (2002) NFAT signaling: choreographing the social lives of cells. Cell 109(Suppl):S67–S79. doi:10.1016/S0092-8674(02)00699-2

    Article  CAS  PubMed  Google Scholar 

  34. Hogan PG, Chen L, Nardone J, Rao A (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17(18):2205–2232. doi:10.1101/gad.1102703

    Article  CAS  PubMed  Google Scholar 

  35. Serfling E, Berberich-Siebelt F, Avots A, Chuvpilo S, Klein-Hessling S, Jha MK et al (2004) NFAT and NF-kappaB factors-the distant relatives. Int J Biochem Cell Biol 36(7):1166–1170. doi:10.1016/j.biocel.2003.07.002

    Article  CAS  PubMed  Google Scholar 

  36. Brabletz T, Pietrowski I, Serfling E (1991) The immunosuppressives FK 506 and cyclosporin A inhibit the generation of protein factors binding to the two purine boxes of the interleukin 2 enhancer. Nucleic Acids Res 19(1):61–67. doi:10.1093/nar/19.1.61

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Berland R, Wortis HH (1998) An NFAT-dependent enhancer is necessary for anti-IgM-mediated induction of murine CD5 expression in primary splenic B cells. J Immunol 161(1):277–285. Available from http://www.jimmunol.org/content/161/1/277.long

  38. Hodge MR, Ranger AM, Charles de la Brousse F, Hoey T, Grusby MJ, Glimcher LH (1996) Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. Immunity 4(4):397–405. doi:10.1016/S1074-7613(00)80253-8

    Article  CAS  PubMed  Google Scholar 

  39. Berland R, Wortis HH (2003) Normal B-1a cell development requires B cell-intrinsic NFATc1 activity. Proc Natl Acad Sci USA 100(23):13459–13464. doi:10.1073/pnas.2233620100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Samanta DN, Palmetshofer A, Marinkovic D, Wirth T, Serfling E, Nitschke L (2005) B cell hyperresponsiveness and expansion of mature follicular B cells but not of marginal zone B cells in NFATc2/c3 double-deficient mice. J Immunol 174(8):4797–4802. doi:10.4049/jimmunol.174.8.4797

    Article  CAS  PubMed  Google Scholar 

  41. Ranger AM, Hodge MR, Gravallese EM, Oukka M, Davidson L, Alt FW et al (1998) Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc. Immunity 8(1):125–134. doi:10.1016/S1074-7613(00)80465-3

    Article  CAS  PubMed  Google Scholar 

  42. Peng SL, Gerth AJ, Ranger AM, Glimcher LH (2001) NFATc1 and NFATc2 together control both T and B cell activation and differentiation. Immunity 14(1):13–20. doi:10.1016/S1074-7613(01)00085-1

    Article  CAS  PubMed  Google Scholar 

  43. Winslow MM, Gallo EM, Neilson JR, Crabtree GR (2006) The calcineurin phosphatase complex modulates immunogenic B cell responses. Immunity 24(2):141–152. doi:10.1016/j.immuni.2005.12.013

    Article  CAS  PubMed  Google Scholar 

  44. Xanthoudakis S, Viola JP, Shaw KT, Luo C, Wallace JD, Bozza PT et al (1996) An enhanced immune response in mice lacking the transcription factor NFAT1. Science 272(5263):892–895. doi:10.1126/science.272.5263.892

    Article  CAS  PubMed  Google Scholar 

  45. Kiani A, Viola JP, Lichtman AH, Rao A (1997) Down-regulation of IL-4 gene transcription and control of Th2 cell differentiation by a mechanism involving NFAT1. Immunity 7(6):849–860. doi:10.1016/S1074-7613(00)80403-3

    Article  CAS  PubMed  Google Scholar 

  46. Schuh K, Kneitz B, Heyer J, Bommhardt U, Jankevics E, Berberich-Siebelt F et al (1998) Retarded thymic involution and massive germinal center formation in NF-ATp-deficient mice. Eur J Immunol 28(8):2456–2466. doi:10.1002/(SICI)1521-4141(199808)28:08<2456:AID-IMMU2456>3.0.CO;2-9

    Article  CAS  PubMed  Google Scholar 

  47. Yoshida H, Nishina H, Takimoto H, Marengère LE, Wakeham AC, Bouchard D et al (1998) The transcription factor NF-ATc1 regulates lymphocyte proliferation and Th2 cytokine production. Immunity 8(1):115–124. doi:10.1016/S1074-7613(00)80464-1

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge Moises Mallo for the production of the transgenic mice. We acknowledge Dr. Pedro Simas for providing us the pµs plasmid. SCP Almeida designed and performed the experiments, generated the transgenic mice colony, and wrote and revised the manuscript. VLO performed the experiments and revised the manuscript. RME Parkhouse designed the project and wrote and revised the manuscript. This work was supported by Fundação para a Ciência e Tecnologia, Ministério da Ciência e Ensino Superior (SFRH/BD/882/2000; POCTI/2000/MGI/36403) and by the Wellcome Trust (WT075813MA).

Conflict of interest

There are no conflicting interests. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

  1. Sílvia Cristina de Paiva e Almeida

    Present address: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisbon, Portugal

  2. Vivian Leite de Oliveira

    Present address: Nucleo de Doenças Infecciosas, Centro de Ciências da Saúde, UFES, Av. Marechal Campos, 1468, Vitória, ES, Brazil

Authors and Affiliations

  1. Instituto Gulbenkian de Ciência, 2780-156, Oeiras, Portugal

    Sílvia Cristina de Paiva e Almeida, Vivian Leite de Oliveira & Robert Michael Evans Parkhouse

Authors
  1. Sílvia Cristina de Paiva e Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vivian Leite de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert Michael Evans Parkhouse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sílvia Cristina de Paiva e Almeida.

Additional information

S. C. P. Almeida and V. L. de Oliveira contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Paiva e Almeida, S.C., de Oliveira, V.L. & Parkhouse, R.M.E. Impact on antibody responses of B-cell-restricted transgenic expression of a viral gene inhibiting activation of NF-κB and NFAT. Arch Virol 160, 1477–1488 (2015). https://doi.org/10.1007/s00705-015-2419-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-015-2419-x

Keywords

Search

Navigation