Skip to main content

Advertisement

SpringerLink
Log in

Co-expression of the Bcl-xL antiapoptotic protein enhances the induction of Th1-like immune responses in mice immunized with DNA vaccines encoding FMDV B and T cell epitopes

  • Original Article
  • Published:
Veterinary Research Communications Aims and scope Submit manuscript

Abstract

Foot-and-mouth disease (FMD) is one of the most devastating animal diseases, affecting all cloven-hoofed domestic and wild animal species. Previous studies from our group using DNA vaccines encoding FMD virus (FMDV) B and T cell epitopes targeted to antigen presenting cells, allowed demonstrating total protection from FMDV homologous challenge in those animals efficiently primed for both humoral and cellular specific responses (Borrego et al. Antivir Res 92:359-363, 2011). In this study, a new DNA vaccine prototype expected to induce stronger and cross-reactive immune responses against FMDV which was designed by making two main modifications: i) adding a new B-cell epitope from the O-serotype to the B and T-cell epitopes from the C-serotype and ii) using a dual promoter plasmid that allowed inserting a new cistron encoding the anti-apoptotic Bcl-xL gene under the control of the internal ribosomal entry site (IRES) of encephalomyocarditis virus aiming to increase and optimize the antigen presentation of the encoded FMDV epitopes after in vivo immunization. In vitro studies showed that Bcl-xL significantly prolonged the survival of DNA transfected cells (p < 0.001). Accordingly, vaccination of Swiss out-bred mice with the dual promoter plasmid increased the total IgG responses induced against each of the FMDV epitopes however no significant differences observed between groups. The humoral immune response was polarized through IgG2a in all vaccination groups (p < 0.05); except peptide T3A; in correspondence with the Th1-like response observed, a clear bias towards the induction of specific IFN-γ secreting CD4+ and CD8+ T cell responses was also observed, being significantly higher (p < 0.05) in the group of mice immunized with the plasmid co-expressing Bcl-xL and the FMDV B and T cell epitopes.

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

  • An LL, Whitton JL (1997) A multivalent minigene vaccine, containing B-Cell, cytotoxic T-Lymphocyte, and Th epitopes from several microbes, induces appropriate responses in vivo and confers protection against more than one pathogen. J Virol 71:2292–2302

    PubMed  CAS  Google Scholar 

  • Argilaguet JM, Perez-Martin E, Gallardo C, Salguero FJ, Borrego B, Lacasta A, Accensi F, Diaz I, Nofrarias M, Pujols J, Blanco E, Perez-Filgueira M, Escribano JM, Rodriguez F (2011) Enhancing DNA immunization by targeting ASFV antigens to SLA-II bearing cells. Vaccine 29:5379–5385. doi:10.1016/j.vaccine.2011.05.084

    Article  PubMed  CAS  Google Scholar 

  • Barnard AL, Arriens A, Cox S, Barnett P, Kristensen B, Summerfield A, McCullough KC (2005) Immune response characteristics following emergency vaccination of pigs against foot-and-mouth disease. Vaccine 23(8):1037–1047. doi:10.1016/j.vaccine.2004.07.034

    Article  PubMed  CAS  Google Scholar 

  • Barteling SJ, Vreeswijk J (1991) Developments in foot-and-mouth disease vaccines. Vaccine 9(2):75–88

    Article  PubMed  CAS  Google Scholar 

  • Blanco E, Garcia-Briones M, Sanz-Parra A, Gomes P, De Oliveira E, Valero ML, Andreu D, Ley V, Sobrino F (2001) Identification of T-cell epitopes in nonstructural proteins of foot-and-mouth disease virus. J Virol 75:3164–3174. doi:10.1128/JVI.75.7.3164-3174.2001

    Article  PubMed  CAS  Google Scholar 

  • Blomer U, Kafri T, Randolph-Moore L, Verma IM, Gage FH (1998) Bcl-xL protects adult septal cholinergic neurons from axotomized cell death. Proc Natl Acad Sci U S A 95(5):2603–2608

    Article  PubMed  CAS  Google Scholar 

  • Borrego B, Fernandez-Pacheco P, Ganges L, Domenech N, Fernandez-Borges N, Sobrino F, Rodriguez F (2006) DNA vaccines expressing B and T cell epitopes can protect mice from FMDV infection in the absence of specific humoral responses. Vaccine 24:3889–3899. doi:10.1016/j.vaccine.2006.02.028

    Article  PubMed  CAS  Google Scholar 

  • Borrego B, Argilaguet JM, Perez-Martin E, Dominguez J, Perez-Filgueira M, Escribano JM, Sobrino F, Rodriguez F (2011) A DNA vaccine encoding foot-and-mouth disease virus B and T-cell epitopes targeted to class II swine leukocyte antigens protects pigs against viral challenge. Antivir Res 92:359–363. doi:10.1016/j.antiviral.2011.07.017

    Article  PubMed  CAS  Google Scholar 

  • Burman A, Clark S, Abrescia NGA, Fry EE, Stuart DI, Jackson T (2006) Specificity of the VP1 GH loop of foot-and-mouth disease virus for αv integrins. J Virol 80:9798–9810. doi:10.1128/JVI.00577-06

    Article  PubMed  CAS  Google Scholar 

  • Cedillo-Barron L, Foster-Cuevas M, Cook A, Gutierrez-Castaneda B, Kollnberger S, Lefevre F, Parkhouse RME (2003) Immunogenicity of plasmids encoding T and B cell epitopes of foot-and-mouth disease virus (FMDV) in swine. Vaccine 21:4261–4269

    Article  PubMed  CAS  Google Scholar 

  • Childerstone A, Cedillo-Baron C, Foster-Cuevas M, Parkhouse M (1999) Demonstration of bovine CD8+ T-cell responses to foot-and mouth disease virus. J Gen Virol 80:663–669

    PubMed  CAS  Google Scholar 

  • Davies G (2002) Foot and mouth disease. Res Vet Sci 73:195–199

    Article  PubMed  Google Scholar 

  • De Diego M, Brocchi E, Mackay D, De Simone F (1997) The non-structural polyprotein 3ABC of foot-and-mouth disease virus as a diagnostic antigen in ELISA to differentiate infected from vaccinated cattle. Arch Virol 142:2021–2033

    Article  PubMed  Google Scholar 

  • Doel TR (2003) FMD vaccines. Virus Res 91:81–99

    Article  PubMed  CAS  Google Scholar 

  • Döşkaya M, Kalantari-Dehaghi M, Walsh CM, Hiszczynska-Sawicka E, Davies DH, Felgner PL, Larsen LS, Lathrop RH, Hatfield GW, Schulz JR, Gürüz Y, Jurnak F (2007) GRA1 protein vaccine confers better immune response compared to codon-optimized GRA1 DNA vaccine. Vaccine 25:1824–1837. doi:10.1016/j.vaccine.2006.10.060

    Article  PubMed  Google Scholar 

  • Fiebig AA, Zhu W, Hollerbach C, Leber B, Andrews DW (2006) Bcl-xL is qualitatively different from and ten times more effective than Bcl-2 when expressed in a breast cancer cell line. BMC Cancer 6:213. doi:10.1186/1471-2407-6-213

    Article  PubMed  Google Scholar 

  • Ganges L, Borrego B, Fernandez-Pacheco P, Revilla C, Fernandez-Borges N, Dominguez J, Sobrino F, Rodriguez F (2011) DNA immunization of pigs with foot-and-mouth disease virus minigenes: from partial protection to disease exacerbation. Virus Res 157:121–125. doi:10.1016/j.virusres.2011.02.003

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Briones MM, Blanco E, Chiva C, Andreu D, Ley V, Sobrino F (2004) Immunogenicity and T cell recognition in swine of foot-and-mouthdisease virus polymerase 3D. J Virol 322:264–275. doi:10.1016/j.virol.2004.01.027

    Article  CAS  Google Scholar 

  • Gil F, Perez-Filgueira M, Barderas MG, Pastor-Vargas C, Alonso G, Vivanco F, Escribano JM (2011) Targeting antigens to an invariant epitope of the MHC Class II DR molecule potentiates the immune response to subunit vaccines. Virus Res 155:55–60. doi:10.1016/j.virusres.2010.08.022

    Article  PubMed  CAS  Google Scholar 

  • Glass EJ, Oliver RA, Collen T, Doel TR, Dimarchi R, Spooner RL (1991) MHC class II restricted recognition of FMDV peptides by bovine T cells. Immunology 74:594–599

    PubMed  CAS  Google Scholar 

  • Grubman MJ, Baxt B (2004) Foot and mouth disease. Clin Microbiol Rev 17:465–493

    Article  PubMed  CAS  Google Scholar 

  • Gulce Iz S, Calımlıoglu B, Deliloglu Gurhan SI (2012) Using Bcl-xL anti-apoptotic protein for altering target cell apoptosis. Electron J Biotechnol 5(5). doi:10.2225/vol15-issue5-fulltext-2

  • Guzman E, Taylor G, Charleston B, Ellis SA (2010) Induction of a cross-reactive CD8(+) T cell response following foot-and-mouth disease virus vaccination. J Virol 84(23):12375–12384. doi:10.1128/JVI.01545-10

    Article  PubMed  CAS  Google Scholar 

  • Huang B, Mao CP, Peng S, He L, Hung CF, Wu TC (2007) Intradermal administration of DNA vaccines combining a strategy to bypass antigen processing with a strategy to prolong dendritic cell survival enhances DNA vaccine potency. Vaccine 25:7824–7831. doi:10.1016/j.vaccine.2007.08.036

    Article  PubMed  CAS  Google Scholar 

  • Joshi G, Sharma R, Kumar Kakker N (2009) Phenotypic and functional characterization of T-cells and in vitro replication of FMDV serotypes in bovine lymphocytes. Vaccine 27:6656–6661. doi:10.1016/j.vaccine.2009.08.107

    Article  PubMed  CAS  Google Scholar 

  • Kim TW, Hung CF, Zheng M, Boyd DAK, He L, Pa SI, Wu TC (2004) A DNA vaccine co-expressing antigen and an anti-apoptotic molecule further enhances the antigen-specific CD8+ T-cell immune response. J Biomed Sci 11:493–499. doi:10.1159/000077899

    PubMed  CAS  Google Scholar 

  • Kim JH, Chen J, Majumder N, Lin H, Falo LD (2005) Survival gene Bcl-xl potentiates DNA-raised antitumor immunity. Gene Ther 12:1517–1525. doi:10.1038/sj.gt.3302584

    Article  PubMed  CAS  Google Scholar 

  • Knowles NJ, Samuel AR, Davies PR, Midgley RJ, Valarcher JF (2005) Pandemic strain of foot-and-mouth disease virus serotype O. Emerg Infect Dis 11:1887–1893

    Article  PubMed  Google Scholar 

  • Kutzler M, Weiner DB (2008) DNA vaccines: ready for prime time? Nat Rev Genet 9:776–788. doi:10.1038/nrg2432

    Article  PubMed  CAS  Google Scholar 

  • Lin F, Shen X, McCoy JR, Mendoza JM, Yan J, Kemmerrer SV, Khan AS, Weiner DB, Broderick KE, Sardesai NY (2011) A novel prototype device for electroporation-enhanced DNA vaccine delivery simultaneously to both skin and muscle. Vaccine 39:6771–6780. doi:10.1016/j.vaccine.2010.12.057

    Article  Google Scholar 

  • Mateu MG (1987) Reactivity with monoclonal antibodies of viruses from an episode of foot-and-mouth disease. Virus Res 8:261–274

    Article  PubMed  CAS  Google Scholar 

  • McCahon D, Crowther DJ, Belsham GJ, Kitson JD, Duchesne M, Have P, Meloen RH, Morgan DO, Simone FD (1989) Evidence for at least four antigenic sites on type O foot-and-mouth disease virus involved in neutralization; identification by single and multiple site monoclonal antibody-resistant mutants. J Gen Virol 70:639–645

    Article  PubMed  CAS  Google Scholar 

  • McCullough K, Sobrino F (2004) Immunology of foot-and-mouth disease Virus. In: McCullough K, Sobrino F (eds) Foot-and-mouth disease virus, current perspectives. Horizon Scientific Press, UK, pp 173–222

    Google Scholar 

  • McCullough KC, Bruckner L, Schaffner R, Fraefel W, Muller HK et al (1992) Relationship between the anti-FMD virus antibody reaction as measured by different assays, and protection in vivo against challenge infection. Vet Microbiol 30:99–112. doi:10.1016/0378-1135(92)90106-4

    Article  PubMed  CAS  Google Scholar 

  • Mingxiao M, Ningyi J, Juan LH, Mina Z, Guoshuna S, Guangze Z, Huijun L, Xiaowei H, Minglan J, Xu L, Haili M, Yue J, Gefen Y, Kuoshi J (2007) Immunogenicity of plasmids encoding P12A and 3C of FMDV and swine IL-18. Antivir Res 76:59–67. doi:10.1016/j.antiviral.2007.05.003

    Article  PubMed  Google Scholar 

  • Murtaugh MP, Foss DL (2002) Inflamatory cytokines and antigen presenting cell activation. Vet Immunol Immunopathol 87:109–121

    Article  PubMed  CAS  Google Scholar 

  • Niborski V, Li Y, Brennan F, Lane M, Torche AM, Remond M, Bonneau M, Riffault S, Stirling C, Hutchings G, Takamatsu H, Barnett P, Charley B, Schwartz-Cornil I (2006) Efficacy of particle-based DNA delivery for vaccination of sheep against FMD. Vaccine 24:7204–7213. doi:10.1016/j.vaccine.2006.06.048

    Article  PubMed  CAS  Google Scholar 

  • Oh Y, Fleming L, Statham B, Hamblin P, Barnett P et al (2012) Interferon-c ınduced by ın vitro re-stimulation of CD4+ T-cells correlates with ın vivo FMD vaccine ınduced protection of cattle against disease and persistent ınfection. PLoS One 7(9):e44365. doi:10.1371/journal.pone.0044365

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez F, Harkins S, Redwine JM, de Pereda JM, Whitton JL (2001) CD4(+) T cells induced by a DNA vaccine: immunological consequences of epitope-specific lysosomal targeting. J Virol 75(21):10421–10430. doi:10.1128/JVI.75.21.10421-10430.2001

    Article  PubMed  CAS  Google Scholar 

  • Rush CM, Mitchell TJ, Garside P (2010) A detailed characterisation of the distribution and presentation of DNA vaccine encoded antigen. Vaccine 28:1620–1634. doi:10.1016/j.vaccine.2009.11.014

    Article  PubMed  CAS  Google Scholar 

  • Saiz M, Gomez S, Martinez-Salas E, Sobrino F (2001) Deletion or substitution of the aphthovirus 3’NCR abrogates infectivity and virus replication. J Gen Virol 82:93–101

    PubMed  CAS  Google Scholar 

  • Sardesai NY, Weiner DB (2011) Electroporation delivery of DNA vaccines: prospects for success. Curr Opin Immunol 23:421–429. doi:10.1016/j.coi.2011.03.008

    Article  PubMed  CAS  Google Scholar 

  • Shi XJ, Wang B, Wang B (2007) Immune enhancing effects of recombinant bovine IL-18 on foot-and-mouth disease vaccination in mice model. Vaccine 25:1257–1264. doi:10.1016/j.vaccine.2006.10.017

    Article  PubMed  CAS  Google Scholar 

  • Sobrino F, Domingo E (2001) Foot-and-mouth disease in Europe, FMD is economically the most important disease of farm animals. Its reemergence in Europe is likely to have consequences that go beyond severe alterations of livestock production and trade. EMBO Rep 459–461

  • Sobrino F, Saiz M, Jimenez-Clavero MA, Nunez JI, Rosas MF et al (2001) Foot-and-mouth disease virus: a long known virus, but a current threat. Vet Res 32:1–30. doi:10.1051/vetres:2001106

    Article  PubMed  CAS  Google Scholar 

  • Su C, Duan X, Wang X, Wang C, Cao R, Zhou B, Chen P (2007) Heterologous expression of FMDV immunodominant epitopes and HSP70 in P. pastoris and the subsequent immune response in mice. Vet Microbiol 124:256–263. doi:10.1016/j.vetmic.2007.04.030

    Article  PubMed  CAS  Google Scholar 

  • Su B, Wang J, Wang X, Jin H, Zhao G, Ding Z, Kang Y, Wang B (2008) The effects of IL-6 and TNF-α as molecular adjuvants on immune responses to FMDV and maturation of dendritic cells by DNA vaccination. Vaccine 26:5111–5122. doi:10.1016/j.vaccine.2008.03.089

    Article  PubMed  CAS  Google Scholar 

  • Wang CY, Chang TY, Walfield AM, Ye J, Shen M, Chen SP, Li MC, Lin YL, Jong MH, Yang PC, Chyr N, Kramer E, Brown F (2002) Effective synthetic peptide vaccine for foot-and-mouth disease in swine. Vaccine 20:2603–2610. doi:10.1016/j.vetmic.2007.05.033

    Article  PubMed  CAS  Google Scholar 

  • Wang F, He XW, Jiang L, Ren D, He Y, Li DA, Sun SH (2006) Enhanced immunogenicity of microencapsulated multiepitope DNA vaccine encoding T and B cell epitopes of foot-and-mouth disease virus in mice. Vaccine 24:2017–2026. doi:10.1016/j.vaccine.2005.11.042

    Article  PubMed  CAS  Google Scholar 

  • Wang JL, Liu MQ, Han J, Chen WZ, Cong W, Cheng G, Gao YH, Lu YG, Chen LJ, Zuo XP, Yan WY, Zheng ZX (2007) A peptide of foot-and-mouth disease virus serotype Asia1 generating a neutralizing antibody response, and an immunostimulatory peptide. Vet Microbiol 125:224–231

    Article  PubMed  CAS  Google Scholar 

  • Wang S, Zhang C, Zhang L, Li J, Huang Z, Lu S (2008) The relative immunogenicity of DNA vaccines delivered by the intramuscular needle injection, electroporation and gene gun methods. Vaccine 26:2100–2110. doi:10.1016/j.vaccine.2008.02.033

    Article  PubMed  CAS  Google Scholar 

  • Weiner DB (2008) DNA vaccines: crossing a line in the sand, Introduction to special issue. Vaccine 26:5073–5074

    Article  PubMed  Google Scholar 

  • Wong HT, Cheng SCS, Chan EWC, Sheng ZT, Yan WY, Zheng ZX, Xie Y (2000) Plasmids encoding foot-and-mouth disease virus VP1 epitopes elicited immune responses in mice and swine and protected swine against viral infection. J Virol 278:27–35. doi:10.1006/viro.2000.0607

    Article  CAS  Google Scholar 

  • Wong HT, Cheng SCS, Sin FWY, Chan EWC, Sheng ZT, Xie Y (2002) A DNA vaccine against foot-and-mouth disease elicits an immune response in swine which is enhanced by co-administration with interleukin-2. Vaccine 20:2641–2647

    Article  PubMed  CAS  Google Scholar 

  • Xiao C, Jin H, Hu Y, Kang Y, Wang J, Du X, Yang Y, She R, Wang B (2007) Enhanced protective efficacy and reduced viral load of foot-and-mouth disease DNA vaccine with co-stimulatory molecules as the molecular adjuvants. Antivir Res 76:11–20. doi:10.1016/j.antiviral.2007.04.002

    Article  PubMed  CAS  Google Scholar 

  • Yang Y, Xiong Z, Zhang S, Yan Y, Nguyen J, Bernard NG, Huifang LU, Brendese J, Yang F, Wang H, Yang XF (2005) Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors. Biochem J 392:135–143. doi:10.1042/BJ20050698

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This project is partly funded by The Scientific and Technological Research Council of Turkey (110O809), Ege University, Science and Technology Center (2011BIL020) and a complementary action between Spain and Turkey (PCI2005-A7-0092). The authors acknowledge EP Martin, Ph.D. and JM Marques, Ph.D. for their technical help. The specific MAbs against FMDV were kindly provided by Emilliana Brocchi, Ph.D., from Istituto Zooprofilattico Sperimentale Della Lombardia, Italy.

Author information

Author notes

  1. Sultan Gülçe İz

    Present address: Department of Bioengineering, Ege University Faculty of Engineering, 35100, Bornova, İzmir, Turkey

Authors and Affiliations

  1. Department of Bioengineering, Ege University Faculty of Engineering, 35100, Bornova, İzmir, Turkey

    İsmet Deliloğlu Gürhan

  2. Department of Parasitology, Ege University Medical School, 35100, Bornova, İzmir, Turkey

    Mert Döşkaya & Yüksel Gürüz

  3. Centro de Investigacion en Sanidad Animal, CISA-INIA, Valdeolmos, 28130, Madrid, Spain

    Belen Borrego

  4. Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain

    Fernando Rodriguez

Authors
  1. Sultan Gülçe İz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mert Döşkaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Belen Borrego
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fernando Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yüksel Gürüz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. İsmet Deliloğlu Gürhan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sultan Gülçe İz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gülçe İz, S., Döşkaya, M., Borrego, B. et al. Co-expression of the Bcl-xL antiapoptotic protein enhances the induction of Th1-like immune responses in mice immunized with DNA vaccines encoding FMDV B and T cell epitopes. Vet Res Commun 37, 187–196 (2013). https://doi.org/10.1007/s11259-013-9560-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11259-013-9560-3

Keywords

Search

Navigation