Skip to main content
SpringerLink
Log in

Cellular Immunology of Sequential Dengue Virus Infection and its Role in Disease Pathogenesis

  • Chapter
  • First Online:
Dengue Virus

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 338))

Abstract

The increased risk for severe dengue disease during secondary dengue virus (DENV) infections, along with the clinical and pathological evidence pointing to cytokines as the proximal mediators of disease, has interested cellular immunologists in exploring the role of DENV-specific T lymphocytes in the pathogenesis of dengue-associated plasma leakage. Recent technological advances in the analysis of virus-specific T cells, applied to blood samples collected before, during and after acute DENV infections, have demonstrated that memory DENV-specific T cells from a prior infection respond with altered cytokine production to heterologous DENV serotypes and that the level of activation and expansion of these memory cells during acute DENV infection correlates with disease severity. Limited data suggest that specific T cell response profiles may predict a higher risk for severe disease during secondary infection. Application of these techniques and principles to animal models and to clinical trials may advance the development of novel therapeutics and protective vaccines.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, McMichael AJ, Davis MM (1996) Phenotypic analysis of antigen-specific T lymphocytes. Science 274:94–96

    Article  CAS  PubMed  Google Scholar 

  • Askonas BA, Taylor PM, Esquivel F (1988) Cytotoxic T cells in influenza infection. Ann N Y Acad Sci 532:230–237

    Article  CAS  PubMed  Google Scholar 

  • Bashyam HS, Green S, Rothman AL (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

    CAS  PubMed  Google Scholar 

  • Beaumier CM, Mathew A, Bashyam HS, Rothman AL (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

    Article  CAS  PubMed  Google Scholar 

  • Catalina MD, Sullivan JL, Brody RM, Luzuriaga K (2002) Phenotypic and functional heterogeneity of EBV epitope-specific CD8+ T cells. J Immunol 168:4184–4191

    CAS  PubMed  Google Scholar 

  • Chen L, Ewing D, Subramanian H, Block K, Rayner J, Alterson KD, Sedegah M, Hayes C, Porter K, Raviprakash K (2007) A heterologous DNA prime-Venezuelan equine encephalitis virus replicon particle boost dengue vaccine regimen affords complete protection from virus challenge in cynomolgus macaques. J Virol 81:11634–11639

    Article  CAS  PubMed  Google Scholar 

  • Dong T, Moran E, Vinh Chau N, Simmons C, Luhn K, Peng Y, Wills B, Phuong Dung N, Thi Thu Thao L, Hien TT, McMichael A, Farrar J, Rowland-Jones S (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

    Article  PubMed  Google Scholar 

  • Endy TP, Chunsuttiwat S, Nisalak A, Libraty DH, Green S, Rothman AL, Vaughn DW, Ennis FA (2002a) Epidemiology of inapparent and symptomatic acute dengue virus infection: a prospective study of primary school children in Kamphaeng Phet, Thailand. Am J Epidemiol 156:40–51

    Article  PubMed  Google Scholar 

  • Endy TP, Nisalak A, Chunsuttiwat S, Libraty DH, Green S, Rothman AL, Vaughn DW, Ennis FA (2002b) Spatial and temporal circulation of dengue virus serotypes: a prospective study of primary school children in Kamphaeng Phet, Thailand. Am J Epidemiol 156:52–59

    Article  PubMed  Google Scholar 

  • Gagnon SJ, Leporati A, Green S, Kalayanarooj S, Vaughn DW, Stephens HA, Suntayakorn S, Kurane I, Ennis FA, Rothman AL (2001) T cell receptor Vbeta gene usage in Thai children with dengue virus infection. Am J Trop Med Hyg 64:41–48

    CAS  PubMed  Google Scholar 

  • Green S, Pichyangkul S, Vaughn DW, Kalayanarooj S, Nimmannitya S, Nisalak A, Kurane I, Rothman AL, Ennis FA (1999a) Early CD69 expression on peripheral blood lymphocytes from children with dengue hemorrhagic fever. J Infect Dis 180:1429–1435

    Article  CAS  PubMed  Google Scholar 

  • Green S, Vaughn DW, Kalayanarooj S, Nimmannitya S, Suntayakorn S, Nisalak A, Lew R, Innis BL, Kurane I, Rothman AL, Ennis FA (1999b) Early immune activation in acute dengue is related to development of plasma leakage and disease severity. J Infect Dis 179:755–762

    Article  CAS  PubMed  Google Scholar 

  • Guy B, Nougarede N, Begue S, Sanchez V, Souag N, Carre M, Chambonneau L, Morrisson DN, Shaw D, Qiao M, Dumas R, Lang J, Forrat R (2008) Cell-mediated immunity induced by chimeric tetravalent dengue vaccine in naive or flavivirus-primed subjects. Vaccine 26:5712–5721

    Article  CAS  PubMed  Google Scholar 

  • Gwinn W, Sun W, Innis BL, Caudill J, King AD (2003) Serotype-specific T(H)1 responses in recipients of two doses of candidate live-attenuated dengue virus vaccines. Am J Trop Med Hyg 69:39–47

    PubMed  Google Scholar 

  • Halstead SB (1989) Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade. Rev Infect Dis 11:S830–S839

    PubMed  Google Scholar 

  • Hammond SN, Balmaseda A, Perez L, Tellez Y, Saborio SI, Mercado JC, Videa E, Rodriguez Y, Perez MA, Cuadra R, Solano S, Rocha J, Idiaquez W, Gonzalez A, Harris E (2005) Differences in dengue severity in infants, children, and adults in a 3-year hospital-based study in Nicaragua. Am J Trop Med Hyg 73:1063–1070

    PubMed  Google Scholar 

  • Hober D, Delannoy AS, Benyoucef S, De Groote D, Wattre P (1996) High levels of sTNFR p75 and TNF alpha in dengue-infected patients. Microbiol Immunol 40:569–573

    CAS  PubMed  Google Scholar 

  • Hober D, Poli L, Roblin B, Gestas P, Chungue E, Granic G, Imbert P, Pecarere JL, Vergez-Pascal R, Wattre P, Maniez-Montreuil M (1993) Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in dengue-infected patients. Am J Trop Med Hyg 48:324–331

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Kalayanarooj S, Vaughn DW, Nimmannitya S, Green S, Suntayakorn S, Kunentrasai N, Viramitrachai W, Ratanachu-eke S, Kiatpolpoj S, Innis BL, Rothman AL, Nisalak A, Ennis FA (1997) Early clinical and laboratory indicators of acute dengue illness. J Infect Dis 176:313–321

    Article  CAS  PubMed  Google Scholar 

  • Koraka P, Benton S, van Amerongen G, Stittelaar KJ, Osterhaus AD (2007) Efficacy of a live attenuated tetravalent candidate dengue vaccine in naive and previously infected cynomolgus macaques. Vaccine 25:5409–5416

    Article  PubMed  Google Scholar 

  • Kurane I, Ennis FA (1992) Immunity and immunopathology in dengue virus infections. Sem Immunol 4:121–127

    CAS  Google Scholar 

  • Kurane I, Innis BL, Nimmannitya S, Nisalak A, Meager A, Janus J, Ennis FA (1991) Activation of T lymphocytes in dengue virus infections. High levels of soluble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon-gamma in sera of children with dengue. J Clin Invest 88:1473–1480

    Article  CAS  PubMed  Google Scholar 

  • Kurane I, Innis BL, Nisalak A, Hoke C, Nimmannitya S, Meager A, Ennis FA (1989a) Human T cell responses to dengue virus antigens. Proliferative responses and interferon gamma production. J Clin Invest 83:506–513

    Article  CAS  PubMed  Google Scholar 

  • Kurane I, Meager A, Ennis FA (1989b) Dengue virus-specific human T cell clones. Serotype crossreactive proliferation, interferon gamma production, and cytotoxic activity. J Exp Med 170:763–775

    Article  CAS  PubMed  Google Scholar 

  • Kurane I, Okamoto Y, Dai LC, Zeng LL, Brinton MA, Ennis FA (1995) Flavivirus-cross-reactive, HLA-DR15-restricted epitope on NS3 recognized by human CD4+ CD8- cytotoxic T lymphocyte clones. J Gen Virol 76:2243–2249

    Article  CAS  PubMed  Google Scholar 

  • Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, Robbins G, Phillips R, Klenerman P, Walker BD (2000) Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 191:1499–1512

    Article  CAS  PubMed  Google Scholar 

  • Livingston PG, Kurane I, Dai LC, Okamoto Y, Lai CJ, Men R, Karaki S, Takiguchi M, Ennis FA (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

    CAS  PubMed  Google Scholar 

  • Loke H, Bethell DB, Phuong CX, Dung M, Schneider J, White NJ, Day NP, Farrar J, Hill AV (2001) Strong HLA class I–restricted T cell responses in dengue hemorrhagic fever: a double-edged sword? J Infect Dis 184:1369–1373

    Article  CAS  PubMed  Google Scholar 

  • Mangada MM, Endy TP, Nisalak A, Chunsuttiwat S, Vaughn DW, Libraty DH, Green S, Ennis FA, Rothman AL (2002) Dengue-specific T cell responses in peripheral blood mononuclear cells obtained prior to secondary dengue virus infections in Thai schoolchildren. J Infect Dis 185:1697–1703

    Article  PubMed  Google Scholar 

  • Mangada MM, Rothman AL (2005) Altered cytokine responses of dengue-specific CD4+ T cells to heterologous serotypes. J Immunol 175:2676–2683

    CAS  PubMed  Google Scholar 

  • Mathew A, Kurane I, Rothman AL, Zeng LL, Brinton MA, Ennis FA (1996) Dominant recognition by human CD8+ cytotoxic T lymphocytes of dengue virus nonstructural proteins NS3 and NS1.2a. J Clin Invest 98:1684–1694

    Article  CAS  PubMed  Google Scholar 

  • Mongkolsapaya J, Dejnirattisai W, Xu X, Vasanawathana S, Tangthawornchaikul N, Chairunsri A, Sawasdivorn S, Duangchinda T, Dong T, Rowland-Jones S, Yenchitsomanus P, McMichael A, Malasit P, Screaton G (2003) Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nature Med 9(7):921–927

    Article  CAS  PubMed  Google Scholar 

  • Mongkolsapaya J, Duangchinda T, Dejnirattisai W, Vasanawathana S, Avirutnan P, Jairungsri A, Khemnu N, Tangthawornchaikul N, Chotiyarnwong P, Sae-Jang K, Koch M, Jones Y, McMichael A, Xu X, Malasit P, Screaton G (2006) T cell responses in dengue hemorrhagic fever: are cross-reactive T cells suboptimal? J Immunol 176:3821–3829

    CAS  PubMed  Google Scholar 

  • Murali-Krishna K, Altman JD, Suresh M, Sourdive DJ, Zajac AJ, Miller JD, Slansky J, Ahmed R (1998) Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8:177–187

    Article  CAS  PubMed  Google Scholar 

  • Panpanich R, Sornchai P, Kanjanaratanakorn K (2006) Corticosteroids for treating dengue shock syndrome. Cochrane Database Syst Rev 3:CD003488

    CAS  PubMed  Google Scholar 

  • Rabablert J, Dharakul T, Yoksan S, Bhamarapravati N (2000) Dengue virus specific T cell responses to live attenuated monovalent dengue-2 and tetravalent dengue vaccines. Asian Pac J Allergy Immunol 18:227–35

    CAS  PubMed  Google Scholar 

  • Rothman AL, Kanesa-thasan N, West K, Janus J, Saluzzo J, Ennis FA (2001) Induction of T lymphocyte responses to dengue virus by a candidate tetravalent live attenuated dengue virus vaccine. Vaccine 19:4694–9

    Article  CAS  PubMed  Google Scholar 

  • Simmons CP, Dong T, Chau NV, Dung NT, Chau TN, Thao-le TT, Hien TT, Rowland-Jones S, Farrar J (2005) Early T-cell responses to dengue virus epitopes in Vietnamese adults with secondary dengue virus infections. J Virol 79:5665–5675

    Article  CAS  PubMed  Google Scholar 

  • Stephens HA, Klaythong R, Sirikong M, Vaughn DW, Green S, Kalayanarooj S, Endy TP, Libraty DH, Nisalak A, Innis BL, Rothman AL, Ennis FA, Chandanayingyong D (2002) HLA-A and -B allele associations with secondary dengue virus infections correlate with disease severity and the infecting viral serotype in ethnic Thais. Tissue Antigens 60:309–18

    Article  CAS  PubMed  Google Scholar 

  • Tan LC, Gudgeon N, Annels NE, Hansasuta P, O'Callaghan CA, Rowland-Jones S, McMichael AJ, Rickinson AB, Callan MF (1999) A re-evaluation of the frequency of CD8+ T cells specific for EBV in healthy virus carriers. J Immunol 162:1827–35

    CAS  PubMed  Google Scholar 

  • Tassniyom S, Vasanawathana S, Chirawatkul A, Rojanasuphot S (1993) Failure of high-dose methylprednisolone in established dengue shock syndrome: a placebo-controlled, double-blind study. Pediatrics 92:111–115

    CAS  PubMed  Google Scholar 

  • Vaughn DW, Green S, Kalayanarooj S, Innis BL, Nimmannitya S, Suntayakorn S, Rothman AL, Ennis FA, Nisalak A (1997) Dengue in the early febrile phase: viremia and antibody responses. J Infect Dis 176:322–330

    Article  CAS  PubMed  Google Scholar 

  • Wills BA, Oragui EE, Stephens AC, Daramola OA, Dung NM, Loan HT, Chau NV, Chambers M, Stepniewska K, Farrar JJ, Levin M (2002) Coagulation abnormalities in dengue hemorrhagic fever: serial investigations in 167 Vietnamese children with Dengue shock syndrome. Clin Infect Dis 35:277–85

    Article  PubMed  Google Scholar 

  • Zhou H, Deem MW (2006) Sculpting the immunological response to dengue fever by polytopic vaccination. Vaccine 24:2451–9

    Article  CAS  PubMed  Google Scholar 

  • Zivna I, Green S, Vaughn DW, Kalayanarooj SH, Stephens AF, Chandanayingyong D, Nisalak A, Ennis FA, Rothman AL (2002) T cell responses to an HLA B*07-restricted epitope on the dengue NS3 protein correlate with disease severity. J Immunol 168:5959–5965

    CAS  PubMed  Google Scholar 

  • Zivny J, DeFronzo M, Jarry W, Jameson J, Cruz J, Ennis FA, Rothman AL (1999) Partial agonist effect influences the CTL response to a heterologous dengue virus serotype. J Immunol 163:2754–2760

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, MA, 01655, USA

    Alan L. Rothman

Authors
  1. Alan L. Rothman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan L. Rothman .

Editor information

Editors and Affiliations

  1. Medical School, University of Massachusetts, Lake Avenue N. 55, Worcester, 01655, U.S.A.

    Alan L. Rothman

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Rothman, A.L. (2010). Cellular Immunology of Sequential Dengue Virus Infection and its Role in Disease Pathogenesis. In: Rothman, A. (eds) Dengue Virus. Current Topics in Microbiology and Immunology, vol 338. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-02215-9_7

Download citation

Publish with us

Policies and ethics

Search

Navigation