1887

Journal of General Virology header logo

Volume 93, Issue 6

Recombinant nucleocapsid-like particles from dengue-2 induce functional serotype-specific cell-mediated immunity in mice Free

Abstract

The interplay of different inflammatory cytokines induced during dengue virus infection plays a role in either protection or increased disease severity. In this sense, vaccine strategies incorporating whole virus are able to elicit both functional and pathological responses. Therefore, an ideal tetravalent vaccine candidate against dengue should be focused on serotype-specific sequences. In the present work, a new formulation of nucleocapsid-like particles (NLPs) obtained from the recombinant dengue-2 capsid protein was evaluated in mice to determine the level of protection against homologous and heterologous viral challenge and to measure the cytotoxicity and cytokine-secretion profiles induced upon heterologous viral stimulation. As a result, a significant protection rate was achieved after challenge with lethal dengue-2 virus, which was dependent on CD4 and CD8 cells. In turn, no protection was observed after heterologous challenge. In accordance, -stimulated spleen cells from mice immunized with NLPs from the four dengue serotypes showed a serotype-specific response of gamma interferon- and tumour necrosis factor alpha-secreting cells. A similar pattern was detected when spleen cells from dengue-immunized animals were stimulated with the capsid protein. Taking these data together, we can assert that NLPs constitute an attractive vaccine candidate against dengue. They induce a functional immune response mediated by CD4 and CD8 cells in mice, which is protective against viral challenge. In turn, they are potentially safe due to two important facts: induction of serotype specific cell-mediated immunity and lack of induction of antiviral antibodies. Further studies in non-human primates or humanized mice should be carried out to elucidate the usefulness of the NLPs as a potential vaccine candidate against dengue disease.

  • Received:
  • Accepted:
  • Published Online:
© 2012 SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.037721-0
2012-06-01
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/6/1204.html?itemId=/content/journal/jgv/10.1099/vir.0.037721-0&mimeType=html&fmt=ahah

References

  1. Balsitis S. J., Williams K. L., Lachica R., Flores D., Kyle J. L., Mehlhop E., Johnson S., Diamond M. S., Beatty P. R., Harris E. 2010; Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLoS Pathog 6:e1000790 [View Article][PubMed]
     [Google Scholar]
  2. Bashyam H. S., Green S., Rothman A. L. 2006; Dengue virus-reactive CD8+ T cells display quantitative and qualitative differences in their response to variant epitopes of heterologous viral serotypes. J Immunol 176:2817–2824[PubMed] [CrossRef]
     [Google Scholar]
  3. Beaumier C. M., Mathew A., Bashyam H. S., Rothman A. L. 2008; Cross-reactive memory CD8+ T cells alter the immune response to heterologous secondary dengue virus infections in mice in a sequence-specific manner. J Infect Dis 197:608–617 [View Article][PubMed]
     [Google Scholar]
  4. Clements D. E., Coller B. A., Lieberman M. M., Ogata S., Wang G., Harada K. E., Putnak J. R., Ivy J. M., McDonell M. other authors 2010; Development of a recombinant tetravalent dengue virus vaccine: immunogenicity and efficacy studies in mice and monkeys. Vaccine 28:2705–2715 [View Article][PubMed]
     [Google Scholar]
  5. Dejnirattisai W., Duangchinda T., Lin C. L., Vasanawathana S., Jones M., Jacobs M., Malasit P., Xu X. N., Screaton G., Mongkolsapaya J. 2008; A complex interplay among virus, dendritic cells, T cells, and cytokines in dengue virus infections. J Immunol 181:5865–5874[PubMed] [CrossRef]
     [Google Scholar]
  6. Dejnirattisai W., Jumnainsong A., Onsirisakul N., Fitton P., Vasanawathana S., Limpitikul W., Puttikhunt C., Edwards C., Duangchinda T. other authors 2010; Cross-reacting antibodies enhance dengue virus infection in humans. Science 328:745–748 [View Article][PubMed]
     [Google Scholar]
  7. Dong T., Moran E., Vinh Chau N., Simmons C., Luhn K., Peng Y., Wills B., Phuong Dung N., Thi Thu Thao L. other authors 2007; High pro-inflammatory cytokine secretion and loss of high avidity cross-reactive cytotoxic T-cells during the course of secondary dengue virus infection. PLoS One 2:e1192 [View Article][PubMed]
     [Google Scholar]
  8. Friberg H., Burns L., Woda M., Kalayanarooj S., Endy T. P., Stephens H. A., Green S., Rothman A. L., Mathew A. 2011; Memory CD8+ T cells from naturally acquired primary dengue virus infection are highly cross-reactive. Immunol Cell Biol 89:122–129 [View Article][PubMed]
     [Google Scholar]
  9. Gagnon S. J., Zeng W., Kurane I., Ennis F. A. 1996; Identification of two epitopes on the dengue 4 virus capsid protein recognized by a serotype-specific and a panel of serotype-cross-reactive human CD4+ cytotoxic T-lymphocyte clones. J Virol 70:141–147[PubMed]
     [Google Scholar]
  10. Gagnon S. J., Ennis F. A., Rothman A. L. 1999; Bystander target cell lysis and cytokine production by dengue virus-specific human CD4+ cytotoxic T-lymphocyte clones. J Virol 73:3623–3629[PubMed]
     [Google Scholar]
  11. Gil L., López C., Lazo L., Valdés I., Marcos E., Alonso R., Gambe A., Martín J., Romero Y. other authors 2009; Recombinant nucleocapsid-like particles from dengue-2 virus induce protective CD4+ and CD8+ cells against viral encephalitis in mice. Int Immunol 21:1175–1183 [View Article][PubMed]
     [Google Scholar]
  12. Green S., Kurane I., Edelman R., Tacket C. O., Eckels K. H., Vaughn D. W., Hoke C. H. Jr, Ennis F. A. 1993; Dengue virus-specific human CD4+ T-lymphocyte responses in a recipient of an experimental live-attenuated dengue virus type 1 vaccine: bulk culture proliferation, clonal analysis, and precursor frequency determination. J Virol 67:5962–5967[PubMed]
     [Google Scholar]
  13. Gunther V. J., Putnak R., Eckels K. H., Mammen M. P., Scherer J. M., Lyons A., Sztein M. B., Sun W. 2011; A human challenge model for dengue infection reveals a possible protective role for sustained interferon gamma levels during the acute phase of illness. Vaccine 29:3895–3904 [View Article][PubMed]
     [Google Scholar]
  14. Guzmán M. G., Alvarez M., Rodríguez R., Rosario D., Vázquez S., Valdés L., Cabrera M. V., Kourí G. 1999; Fatal dengue hemorrhagic fever in Cuba, 1997. Int J Infect Dis 3:130–135 [View Article][PubMed]
     [Google Scholar]
  15. Halstead S. B. 1988; Pathogenesis of dengue: challenges to molecular biology. Science 239:476–481 [View Article][PubMed]
     [Google Scholar]
  16. Halstead S. B. 1989; Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade. Rev Infect Dis 11:Suppl. 4S830–S839 [View Article][PubMed]
     [Google Scholar]
  17. Hatch S., Endy T. P., Thomas S., Mathew A., Potts J., Pazoles P., Libraty D. H., Gibbons R., Rothman A. L. 2011; Intracellular cytokine production by dengue virus-specific T cells correlates with subclinical secondary infection. J Infect Dis 203:1282–1291 [View Article][PubMed]
     [Google Scholar]
  18. Imrie A., Meeks J., Gurary A., Sukhbataar M., Kitsutani P., Effler P., Zhao Z. 2007; Differential functional avidity of dengue virus-specific T-cell clones for variant peptides representing heterologous and previously encountered serotypes. J Virol 81:10081–10091 [View Article][PubMed]
     [Google Scholar]
  19. Irie K., Mohan P. M., Sasaguri Y., Putnak R., Padmanabhan R. 1989; Sequence analysis of cloned dengue virus type 2 genome (New Guinea-C strain). Gene 75:197–211 [View Article][PubMed]
     [Google Scholar]
  20. Kaufman B. M., Summers P. L., Dubois D. R., Eckels K. H. 1987; Monoclonal antibodies against dengue 2 virus E-glycoprotein protect mice against lethal dengue infection. Am J Trop Med Hyg 36:427–434[PubMed]
     [Google Scholar]
  21. Khan A. M., Heiny A. T., Lee K. X., Srinivasan K. N., Tan T. W., August J. T., Brusic V. 2006; Large-scale analysis of antigenic diversity of T-cell epitopes in dengue virus. BMC Bioinformatics 7:Suppl. 5S4 [View Article][PubMed]
     [Google Scholar]
  22. Khan A. M., Miotto O., Nascimento E. J., Srinivasan K. N., Heiny A. T., Zhang G. L., Marques E. T., Tan T. W., Brusic V. other authors 2008; Conservation and variability of dengue virus proteins: implications for vaccine design. PLoS Negl Trop Dis 2:e272 [View Article][PubMed]
     [Google Scholar]
  23. Khromykh A. A., Westaway E. G. 1996; RNA binding properties of core protein of the flavivirus Kunjin. Arch Virol 141:685–699 [View Article][PubMed]
     [Google Scholar]
  24. Kuhn R. J., Zhang W., Rossmann M. G., Pletnev S. V., Corver J., Lenches E., Jones C. T., Mukhopadhyay S., Chipman P. R., Strauss E. G. 2002; Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell 108:717–725 [View Article][PubMed]
     [Google Scholar]
  25. Lazo L., Hermida L., Zulueta A., Sánchez J., López C., Silva R., Guillén G., Guzmán M. G. 2007; A recombinant capsid protein from dengue-2 induces protection in mice against homologous virus. Vaccine 25:1064–1070 [View Article][PubMed]
     [Google Scholar]
  26. Libraty D. H., Endy T. P., Houng H. S., Green S., Kalayanarooj S., Suntayakorn S., Chansiriwongs W., Vaughn D. W., Nisalak A. other authors 2002; Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections. J Infect Dis 185:1213–1221 [View Article][PubMed]
     [Google Scholar]
  27. Livingston P. G., Kurane I., Dai L. C., Okamoto Y., Lai C. J., Men R., Karaki S., Takiguchi M., Ennis F. A. 1995; Dengue virus-specific, HLA-B35-restricted, human CD8+ cytotoxic T lymphocyte (CTL) clones. Recognition of NS3 amino acids 500 to 508 by CTL clones of two different serotype specificities. J Immunol 154:1287–1295[PubMed]
     [Google Scholar]
  28. López C., Gil L., Lazo L., Menéndez I., Marcos E., Sánchez J., Valdés I., Falcón V., de la Rosa M. C. other authors 2009; In vitro assembly of nucleocapsid-like particles from purified recombinant capsid protein of dengue-2 virus. Arch Virol 154:695–698 [View Article][PubMed]
     [Google Scholar]
  29. Mangada M. M., Rothman A. L. 2005; Altered cytokine responses of dengue-specific CD4+ T cells to heterologous serotypes. J Immunol 175:2676–2683[PubMed] [CrossRef]
     [Google Scholar]
  30. Mathew A., Kurane I., Rothman A. L., Zeng L. L., Brinton M. A., Ennis F. A. 1996; Dominant recognition by human CD8+ cytotoxic T lymphocytes of dengue virus nonstructural proteins NS3 and NS1.2a. J Clin Invest 98:1684–1691 [View Article][PubMed]
     [Google Scholar]
  31. Mongkolsapaya J., Dejnirattisai W., Xu X. N., Vasanawathana S., Tangthawornchaikul N., Chairunsri A., Sawasdivorn S., Duangchinda T., Dong T. other authors 2003; Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med 9:921–927 [View Article][PubMed]
     [Google Scholar]
  32. Mongkolsapaya J., Duangchinda T., Dejnirattisai W., Vasanawathana S., Avirutnan P., Jairungsri A., Khemnu N., Tangthawornchaikul N., Chotiyarnwong P. other authors 2006; T cell responses in dengue hemorrhagic fever: are cross-reactive T cells suboptimal?. J Immunol 176:3821–3829[PubMed] [CrossRef]
     [Google Scholar]
  33. Morens D. M. 1994; Antibody-dependent enhancement of infection and the pathogenesis of viral disease. Clin Infect Dis 19:500–512 [View Article][PubMed]
     [Google Scholar]
  34. Morens D. M., Halstead S. B., Repik P. M., Putvatana R., Raybourne N. 1985; Simplified plaque reduction neutralization assay for dengue viruses by semimicro methods in BHK-21 cells: comparison of the BHK suspension test with standard plaque reduction neutralization. J Clin Microbiol 22:250–254[PubMed]
     [Google Scholar]
  35. Mukhopadhyay S., Kuhn R. J., Rossmann M. G. 2005; A structural perspective of the flavivirus life cycle. Nat Rev Microbiol 3:13–22 [View Article][PubMed]
     [Google Scholar]
  36. Riedl P., Stober D., Oehninger C., Melber K., Reimann J., Schirmbeck R. 2002; Priming Th1 immunity to viral core particles is facilitated by trace amounts of RNA bound to its arginine-rich domain. J Immunol 168:4951–4959[PubMed] [CrossRef]
     [Google Scholar]
  37. Rothman A. L. 2003; Immunology and immunopathogenesis of dengue disease. Adv Virus Res 60:397–419 [View Article][PubMed]
     [Google Scholar]
  38. Rothman A. L. 2004; Dengue: defining protective versus pathologic immunity. J Clin Invest 113:946–951[PubMed] [CrossRef]
     [Google Scholar]
  39. Sabin A. B. 1952; Research on dengue during World War II. Am J Trop Med Hyg 1:30–50[PubMed]
     [Google Scholar]
  40. Sangkawibha N., Rojanasuphot S., Ahandrik S., Viriyapongse S., Jatanasen S., Salitul V., Phanthumachinda B., Halstead S. B. 1984; Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am J Epidemiol 120:653–669[PubMed]
     [Google Scholar]
  41. Shresta S., Kyle J. L., Snider H. M., Basavapatna M., Beatty P. R., Harris E. 2004; Interferon-dependent immunity is essential for resistance to primary dengue virus infection in mice, whereas T- and B-cell-dependent immunity are less critical. J Virol 78:2701–2710 [View Article][PubMed]
     [Google Scholar]
  42. Simmons M., Nelson W. M., Wu S. J., Hayes C. G. 1998; Evaluation of the protective efficacy of a recombinant dengue envelope B domain fusion protein against dengue 2 virus infection in mice. Am J Trop Med Hyg 58:655–662[PubMed]
     [Google Scholar]
  43. Takeshita F., Leifer C. A., Gursel I., Ishii K. J., Takeshita S., Gursel M., Klinman D. M. 2001; Cutting edge: role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. J Immunol 167:3555–3558[PubMed] [CrossRef]
     [Google Scholar]
  44. van der Most R. G., Murali-Krishna K., Ahmed R., Strauss J. H. 2000; Chimeric yellow fever/dengue virus as a candidate dengue vaccine: quantitation of the dengue virus-specific CD8 T-cell response. J Virol 74:8094–8101 [View Article][PubMed]
     [Google Scholar]
  45. van der Most R. G., Murali-Krishna K., Ahmed R. 2003; Prolonged presence of effector-memory CD8 T cells in the central nervous system after dengue virus encephalitis. Int Immunol 15:119–125 [View Article][PubMed]
     [Google Scholar]
  46. Vollmer J. 2006; CpG motifs to modulate innate and adaptive immune responses. Int Rev Immunol 25:125–134 [View Article][PubMed]
     [Google Scholar]
  47. Yauch L. E., Shresta S. 2008; Mouse models of dengue virus infection and disease. Antiviral Res 80:87–93 [View Article][PubMed]
     [Google Scholar]
  48. Yauch L. E., Zellweger R. M., Kotturi M. F., Qutubuddin A., Sidney J., Peters B., Prestwood T. R., Sette A., Shresta S. 2009; A protective role for dengue virus-specific CD8+ T cells. J Immunol 182:4865–4873 [View Article][PubMed]
     [Google Scholar]
  49. Yauch L. E., Prestwood T. R., May M. M., Morar M. M., Zellweger R. M., Peters B., Sette A., Shresta S. 2010; CD4+ T cells are not required for the induction of dengue virus-specific CD8+ T cell or antibody responses but contribute to protection after vaccination. J Immunol 185:5405–5416 [View Article][PubMed]
     [Google Scholar]
  50. Zellweger R. M., Prestwood T. R., Shresta S. 2010; Enhanced infection of liver sinusoidal endothelial cells in a mouse model of antibody-induced severe dengue disease. Cell Host Microbe 7:128–139 [View Article][PubMed]
     [Google Scholar]
  51. Zivny J., DeFronzo M., Jarry W., Jameson J., Cruz J., Ennis F. A., Rothman A. L. 1999; Partial agonist effect influences the CTL response to a heterologous dengue virus serotype. J Immunol 163:2754–2760
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.037721-0
Loading
Recombinant nucleocapsid-like particles from dengue-2 induce functional serotype-specific cell-mediated immunity in mice
J. Gen. Virol. 93, 1204 (2012); https://doi.org/10.1099/vir.0.037721-0
/content/journal/jgv/10.1099/vir.0.037721-0
/content/journal/jgv/10.1099/vir.0.037721-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed

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