Gaceta Médica de México

Contents by Year, Volume and Issue

Table of Contents

General Information

Instructions for Authors

Message to Editor

Editorial Board

>Journals >Gaceta Médica de México >Year 2013, Issue 5

Castro-Mussot ME, Machain-Williams C, Loroño-Pino MA, Salazar MI
Immune responses and immunopathogenesis in infections with dengue virus
Gac Med Mex 2013; 149 (5)

Language: Español
References: 100
Page: 531-540
PDF: 148.94 Kb.

Full text


We still have an incomplete understanding of both immunoprotection and immunopathogenesis mechanisms in dengue. Proper balance among the components of the immune response plays an important role in protection as well as in pathogenesis because these impact clinical outcomes and severity of dengue cases. In this article, we review the elements of the immune response that participate in DENV infections, and we contrast the levels of immune effectors in both classic dengue fever and the severe dengue fever cases. We also emphasize the components frequently related to the immunopathogenesis in dengue. It is clear that several effectors are increased or dysregulated in the severe cases. Finally, the global mechanism that contributes to the subversion of the immune system in dengue hemorrhagic fever or dengue shock syndrome still requires complete elucidation.

Key words: Dengue, Immunity, Immunopathogenesis.


  1. Rodríguez-Madoz J, Belicha-Villanueva A, Bermal-Rubio D, Ashour J, Ayllon J, Fernandez-Sesma A. Inhibition of the type I interferon response in human dendritic cells by dengue virus infection requires a catalytically active NS2B3 complex. J Virol. 2010;84:9760-74.

  2. Morrison J, Aguirre S, Fernandez Sesma A. Innate immunity evasion by dengue virus. Viruses. 2012;4:397.

  3. Ho LJ, Hung LF, Weng CY, et al. Dengue virus type 2 antagonizes IFNalpha but not IFN-gamma antiviral effect via down-regulating Tyk2-STAT signaling in the human dendritic cell. J Immunol. 2005;174:8163-72.

  4. Muñoz-Jordán JL, Laurent-Rolle M, Ashour J, et al. Inhibition of alpha/beta interferon signaling by the NS4B protein of flaviviruses. J Virol. 2005;79:8004-13.

  5. Mazzon M, Jones M, Davidson A, Chain B, Jacobs M. Dengue virus NS5 inhibits interferon-alpha signaling by blocking signal transducer and activator of transcription 2 phosphorylation. J Infect Dis. 2009;200: 1261-70.

  6. Ashour J, Laurent-Rolle M, Shi PY, García-Sastre A. NS5 of dengue virus mediates STAT2 binding and degradation. J Virol. 2009;83:5408-18.

  7. Perry ST, Buck MD, Lada SM, Schindler C, Shresta S. STAT2 Mediates innate immunity to dengue virus in the absence of STAT1 via the type I interferon receptor. PLoS Pathog. 2011;7(2):e1001297.

  8. Goldsby R, Kindt T, Osborne B, Kuby J. Inmunology. 6.a ed. Nueva York: WH Freeman and Co.; 2007.

  9. Lobgis M, Mûllbacher A, Lee E. Evidence that a mechanism for efficient flavivirus budding upregulates MHC class I. Immunol Cell Biol. 2004;82:184-8.

  10. Hershkovitz O, Zilka A, Bar-Ilan A, et al. Dengue virus replicon expressing the nonstructural proteins suffices to enhance membrane expression of HLA class I and inhibit lysis by human NK cells. J Virol. 2008;82:7666-76.

  11. Kurane I, Hebblewaite D, Ennis F. Characterization with monoclonal antibodies of human lymphocytes active in natural killing and antibodydependent cell-mediated cytotoxicity of dengue virus-infected cells. Immunology. 1986;58:429-36.

  12. Azeredo EL, De Oliveira-Pinto LM, Zagne SM, Cerqueira DIS, Nogueira RMR, Kubelka CF. NK cells, displaying early activation, cytotoxicity and adhesion molecules, are associated with mild dengue disease. Clin Exp Immunol. 2006;143:345-56.

  13. Chaturvedi UC, Nagar R, Mathur A. Effect of dengue virus infection on Fc-receptor functions of mouse macrophages.J Gen Virol. 1983;64: 2399-407.

  14. Charnsilpa W, Takhampunya R, Endy TP, Mammen MP, Libraty DH, Ubol S. Nitric oxide radical suppresses replication of wild-type dengue 2 viruses in vitro. J Med Virol. 2005;77:89-95.

  15. Takhampunya R, Padmanabhan R, Ubol S. Antiviral action of nitric oxide on dengue virus type 2 replication. J Gen Virol. 2006;87:3003-11.

  16. Chaturvedi U, Nagar R. Nitric oxide in dengue and dengue haemorrhagic fever: necessity or nuisance? FEMS Immunol Med Microbiol. 2009;56:9-24.

  17. Avirutnan P, Fuchs A, Hauhart RE, et al. Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. J Exp Med. 2010;20:793-806.

  18. Bokisch VA, Muller-Eberhard HJ, Dixon FJ. The role of complement in hemorrhagic shock syndrome (dengue). Trans Assoc Am Physicians. 1973;86:102-10.

  19. Dalrymple NA, Mackow ER. Endothelial cells elicit immune-enhancing responses to dengue virus infection. J Virol. 2012;86:6408-15.

  20. Avirutnan P, Punyadee N, Noisakran S, et al. Vascular leakage in severe dengue virus infection a potential role for the nonstructural viral protein NS1 and complement. J Infect Dis. 2006;193:1078-88.

  21. Cheng HJ, Lin CF, Lei HY, et al. Proteomic analysis of endothelial cell autoantigens recognized by anti-dengue virus nonstructural protein 1 antibodies. Exp Biol Med. 2009;234:63-73.

  22. Nascimiento EJ, Silva AM, Cordeiro MT, et al. Alternative complement pathway deregulation is correlated with dengue severity. PLoS One. 2009;4(8):e6782.

  23. Avirutnan P, Hauhart RE, Somnuke P, Blom AM, Diamond MS, Atkinson JP. Binding of flavivirus nonstructural protein NS1 to C4b binding protein modulates complement activation. J Immunol. 2011;187:424-33.

  24. Shresta S. Role of complement in dengue virus infection: protection or pathogenesis? MBio. 2012;3:e00003-12.

  25. Garred P, Larsen F, Madsen HO, Koch C. Mannose-binding lectin deficiency revisited. Mol Immunol. 2003;40:73-84.

  26. Chase AJ, Medina FA, Muñoz-Jordán JL. Impairment of CD4+ T cell polarization by dengue virus-infected dendritic cells. J Infect Dis. 2011;203:1763-74.

  27. Mongkolsapaya J, Duangchinda T, Dejnirattisai W, et al. T cell responses in dengue hemorrhagic fever: are cross-reactive T cells suboptimal?. J Immunol. 2006;176:3821-9.

  28. Yauch LE, Zellweger RM, Kotturi MF, et al. A protective role for dengue virus-specific CD8+ T cells. J Immunol. 2009;182:4865-73.

  29. Friberg H, Burns L, Woda M, et al. Memory CD8+ T cells from naturally acquired primary dengue virus infection are highly cross-reactive. Immunol Cell Biol. 2011;89:122-9.

  30. Myint KS, Endy TP, Mongkolsirichaikul D, et al. Cellular immune activation in children with acute dengue virus infections is modulated by apoptosis. J Infect Dis. 2006;194:600-7.

  31. Mladinich KM, Piaskowski SM, Rudersdorf R, et al. Dengue virus-specific CD4+ and CD8+ T lymphocytes target NS1, NS3 and NS5 in infected Indian rhesus macaques. Immunogenetics. 2012;64:111-21.

  32. Lünh K, Simmons C, Moram E, et al. Increased frequencies of CD4+, CD25high regulatory T cells in acute dengue infection. J Exp Med. 2007;204:979-85.

  33. McBride W. Evaluation of dengue NS1 test kits for the diagnosis of dengue fever. Diagn Microb Infect Dis. 2009;64:31-6.

  34. Smith SA, Zhou Y, Olivarez NP, Broadwater AH, Da Silva AM, Crowe JE Jr. Persistence of circulating memory B cells clones with potential for dengue virus disease enhancement for decates following the infection. J Virol. 2012;86:2665-72.

  35. Scott RM, Nimmannitya S, Bancroft WH, Mansuwan P. Shock syndrome in primary dengue infections. Am J Trop Med Hyg. 1976;25:866-74.

  36. Talarmin A, Labeau B, Lelarge J, Sarthou JL. Immunoglobulin A-specific capture enzyme-linked immunosorbent assay for diagnosis of dengue fever. J Clin Microbiol. 1998;36:1189-92.

  37. Balmaseda A, Guzmán MG, Hammond S, et al. Diagnosis of dengue virus infection by detection of specific immunoglobulin M (IgM) and IgA antibodies in serum and saliva. Clin Diagn Lab Immunol. 2003;10:317-22.

  38. Nawa M, Takasaki T, Ito M, Inoue S, Morita K, Kurane I. Immunoglobulin A antibody responses in dengue patients: a useful marker for serodiagnosis of dengue virus infection. Clin Diagn Lab Immunol. 2005;12:1235-7.

  39. Chareonsirisuthigul T, Kalayanarooj S, Ubol S. Dengue virus (DENV) antibody-dependent enhancement of infection upregulates the production of anti-inflammatory cytokines, but suppresses anti-DENV free radical and pro-inflammatory cytokine production in THP-1 cells. J Gen Virol. 2007;88:365-75.

  40. Halstead S, Rojanasuphot R, Sangkawibha N. Original antigenic sin in dengue. Am J Trop Med Hyg. 1983;32:154-6.

  41. Mongkolsapaya J, Dejnirattisai W, Xu XN, et al. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med. 2003;9:912-7.

  42. Midgley CM, Bajwa-Joseph M, Vasanawathana S, et al. An in-depth analysis of original antigenic sin in dengue virus infection. J Virol. 2011;85:410-21.

  43. Lazaro-Olán L, Mellado-Sánchez G, García-Cordero J, et al. Analysis of antibody response in human dengue patients from the Mexican coast using recombinant antigens. Vector Borne Zoonotic Dis. 2008;8:69-79.

  44. Malavige G, Fernando S, Seneviratne S. Dengue viral infections. Postgrad Med J. 2004;80:588-601.

  45. Mathew A, Rothman A. Understanding the contribution of celular immunity to dengue disease pathogenesis. Immunol Rev. 2008;225: 300-13.

  46. Hober D, Poli L, Roblin B, et al. Serum levels of tumor necrosis factoralpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) in dengue-infected patients. Am J Trop Med Hyg. 1993;48:324-31.

  47. Kuno G, Bailey RE. Cytokine responses to dengue infection among Puerto Rican patients. Mem Inst Oswaldo Cruz. 1994;89:179-82.

  48. Raghupathy R, Chaturvedi UC, Al-Sayer H, et al. Elevated levels of IL-8 in dengue hemorrhagic fever. J Med Virol. 1998;56:280-5.

  49. Chaturvedi U, Nagar R, Shrivastava R. Macrophage & dengue virus: friend or foe? Indian J Med Res. 2006;124:23-40.

  50. Braga EL, Moura P, Pinto LM, et al. Detection of circulant tumor necrosis factor-alpha, soluble tumor necrosis factor p75 and interferon-gamma in Brazilian patients with dengue fever and dengue hemorrhagic fever. Mem Inst Oswaldo Cruz. 2001;96:229-32.

  51. Juffrie M, van Der Meer GM, Hack CE, et al. Inflammatory mediators in dengue virus infection in children: interleukin-8 and its relationship to neutrophil degranulation. Infect Immun. 2000;68:702-7.

  52. Priyadarshini D, Gadia RR, Tripathy A, et al. Clinical findings and proinflammatory cytokines in dengue patients in Western India: a facilitybased study. PLoS One. 2010;5(1):e8709.

  53. Wang L, Chen R, Liu J, Yu H, Kuo H, Yang K. Implications of dynamic changes among tumor necrosis factor  (TNF-), membrane TNF receptor, and soluble TNF receptor levels in regard to the severity of dengue infection. Am J Trop Med Hyg. 2007;77:297-302.

  54. Mustafa AS, Elbishbishi EA, Agarwal R, Chaturvedi UC. Elevated levels of interleukin-13 and IL-18 in patients with dengue hemorrhagic fever. FEMS Immunol Med Microbiol. 2001;30(3):229-33.

  55. Worral NK, Chang K, Lejeune WS, et al. TNF- causes reversible in vivo systemic vascular barrier dysfunction via NO-dependent and independent mechanisms. Am J Physiol Heart Circ Physiol. 1997;273:H2565-74.

  56. Chen HC, Hofman FM, Kung JT, Lin YD, Wu-Hsieh BA. Both virus and tumor necrosis factor alpha are critical for endothelium damage in a mouse model of dengue virus-induced hemorrhage. J Virol. 2007;81:5518-26.

  57. Wati S, Li P, Burrell C, Carr J. Dengue virus (DV) replication in monocytederived macrophages is not affected by tumor necrosis factor alpha (TNF-), and DV infection induces altered responsiveness to TNF- stimulation. J Virol. 2007;81:10161-71.

  58. Yen YT, Chen HC, Lin YD, Shieh CC, Wu-Hsieh BA. Enhancement by tumor necrosis factor alpha of dengue virus-induced endothelial cell production of reactive nitrogen and oxygen species is key to hemorrhage development. J Virol. 2008;82:12312-24.

  59. Lin CF, Lei HY, Shiau AL, et al. Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide. J Immunol. 2002;169:657-64.

  60. Lin YS, Yeh TM, Lin CF, et al. Molecular mimicry between virus and host and its implications for dengue disease pathogenesis. Exp Biol Med. 2011;236:515-23.

  61. Green S, Vaugh DW, Kalanarooj S, et al. Early immune activation in acute dengue illness is related to development of plasma leakage and disease severity. J Infect Dis. 1999;179:755-62.

  62. Fernández-Mestre MT, Gendzekhadze K, Rivas-Vetencourt P, Layrisse Z. TNF-alpha-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens. 2004;64(4): 469-72.

  63. Lin C, Chiu S, Hsiao Y, et al. Expression of cytokine, chemokine, and adhesion molecules during endothelial cell activation induced by antibodies against dengue virus nonstructural protein 1. J Immunol. 2005;174:395-403.

  64. Restrepo B, Ramirez R, Arboleda M, Alvarez G, Ospina M, Diaz F. Serum levels of cytokines in two ethnic groups with dengue virus infection. Am J Trop Med Hyg. 2008;79:673-7.

  65. Ubol S, Masrinoul P, Chaijaruwanich J, Kalayanarooj S, Charoensirisuthikul T, Kasisith J. Differences in global gene expression in peripheral blood mononuclear cells indicate a significant role of the innate responses in progression of dengue fever but not dengue hemorrhagic fever. J Infect Dis. 2008;197:1459-67.

  66. Soemanto BE, Hasebe F, Igarashi A. Infection of dengue 2 virus strains isolated from patients exhibiting different disease severities to human peripheral blood leukocytes and production of cytokines in the infected culture supernatant. Southeast Asian J Trop Med Public Health. 1999;30:729-34.

  67. Bosch I, Xhaja K, Estevez L, et al. Increased production of interleukin-8 in primary human monocytes and in human epithelial and endothelial cell lines after dengue virus challenge. J Virol. 2002;76:5588-97.

  68. Medin C, Rothman A. Cell type-specific mechanisms of interleukin-8 induction by dengue virus and differential response to drug treatment. J Infec Dis. 2006;193:1070-77.

  69. Chen YC, Wang SY. Activation of terminally differentiated human monocytes/ macrophages by dengue virus: productive infection, hierarchical production of innate cytokines and chemokines, and the synergistic effect of lipopolysaccharide. J Virol. 2002;76:9877-87.

  70. Medin CL, Fitzgerald KA, Rothman AL. Dengue virus nonstructural protein NS5 induces interleukin-8 transcription and secretion. J Virol. 2005;79:11053-061.

  71. King CA, Anderson R, Marshall JS. Dengue virus selectively induces human mast cell chemokine production. J Virol. 2002;76(16): 8408-19.

  72. Suksanpaisan L, Cabrera-Hernandez A, Smith DR. Infection of human primary hepatocytes with dengue virus serotype 2. J Med Virol. 2007;79:300-7.

  73. Conceição TM, El-Bacha T, Villas-Bôas CS, et al. Gene expression analysis during dengue virus infection in HepG2 cells reveals virus control of innate immune response. J Infect. 2010;60:65-75.

  74. Swanson BJ, Murakami M, Mitchell TC, Kappler J, Marrack P. RANTES production by memory phenotype T cells is controlled by a posttranscriptional, TCR-dependent process. Immunity. 2002;17:605-15.

  75. Lin YL, Liu CC, Chuang JI, et al. Involvement of oxidative stress, NF-IL-6 and RANTES expression in dengue-2-virus-infected human liver cells. Virology. 2000;276:114-26.

  76. Becquart P, Wauquier N, Nkoghe D, et al. Acute dengue virus 2 infection in Gabonese patients is associated with an early innate immune response, including strong interferon alpha production. BMC Infect Dis. 2010;10:356.

  77. Pérez AB, García G, Sierra B, et al. IL-10 levels in Dengue patients: some findings from the exceptional epidemiological conditions in Cuba. J Med Virol. 2004;73(2):230-4.

  78. Spain-Santana TA, Marglin S, Ennis FA, Rothman AL. MIP-1 alpha and MIP-1 beta induction by dengue virus. J Med Virol. 2001;65:324-30.

  79. Kurane I, Innis BL, Nimmannitya S, et al. 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. 1991;88:1473-80.

  80. Fadilah SA, Sahir S, Raymond A, Cheong SK, Aziz JA, Sivagengei K. Quantitation of T lymphocyte subsets helps to distinguish dengue hemorrhagic fever from classic dengue fever during the acute febrile stage. Southeast Asian J Med Public Health. 1999;4:710-7.

  81. Kurane I, Matsutani T, Suzuki R, et al. T-cells responses to dengue virus in humans. Trop Med Health. 2011;39:45-51.

  82. Monteiro SP, do Brasil PE, Cabello GM, et al. HLA-A*01 allele: a risk factor for dengue haemorrhagic fever in Brazil’s population. Mem Inst Oswaldo Cruz. 2012;107:224-30.

  83. Chiewsilp P, Scott RM, Bhamarapravati N. Histocompatibility antigens and dengue hemorrhagic fever. Am J Trop Med Hyg. 1981;30:1100-5.

  84. Brown MG, Salas RA, Vickers IE, Heslop OD, Smikle MF. Dengue HLA associations in Jamaicans. West Indian Med J. 2011;60:126-31.

  85. Loke H, Bethell DB, Phuong CX, et al. Strong HLA class I-restricted T cell responses in dengue hemorrhagic fever: a double-edged sword? J Infect Dis. 2001;184:1369-73.

  86. Nguyen TP, Kikuchi M, Vu TQ, et al. Protective and enhancing HLA alleles, HLA-DRB1*0901 and HLA-A*24, for severe forms of dengue virus infection, dengue hemorrhagic fever and dengue shock syndrome. PLoS Negl Trop Dis. 2008;2(10):e304.

  87. Paradoa Pérez ML, Trujillo Y, Basanta P. Association of dengue hemorrhagic fever with the HLA system. Hematologia (Budap). 1987;20:83-7.

  88. Sierra B, Alegre R, Perez A, et al. HLA-A, -B, -C, and DRB1 allele frequencies in cuban individuals with antecedents of dengue 2 disease: advantages of the Cuban population for HLA studies of dengue virus infection. Hum Immunol. 2007;68:531-40.

  89. Malavige GN, Rostron T, Rohanachandra LT, et al. HLA class I and class II associations in dengue viral infections in a Sri Lankan population. PloS ONE. 2011;6(6):e20581.

  90. Stephens H, Klaythong R, Sirikong M, et al. 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. 2002;60:309-18.

  91. LaFleur C, Granados J, Vargas-Alarcon G, et al. HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever. Hum Immunol. 2002;63:1039-44.

  92. Appana R, Huat T, Lum L, Lay P, Vadivelu J, Devi S. Cross-reactive T-cell responses to the nonstructural regions of dengue viruses among dengue fever and dengue hemorrhagic fever patients in Malaysia. Clin Vaccine Immunol. 2007;14:969-77.

  93. Othman S, Rahman NA, Yusof R. Induction of MHC Class I HLA-A2 promoter by dengue virus occurs at the NFB binding domains of the Class I regulatory complex. Virus Res. 2012;163:238-45.

  94. Oliveira EVL, Curry-Pontes ERJ, Cunha RV, Bucker-Fróes I, Nascimento D. Hematological abnormalities in patients with dengue. Rev Soc Bras Med Trop. 2009;42:682-5.

  95. Biswas HH, Ortega O, Gordon A, et al. Early clinical features of dengue virus infection in nicaraguan children: a longitudinal analysis. PLoS Negl Trop Dis. 2012;6(3):e1562.

  96. Huang YH, Chang BI, Lei HY, et al. Antibodies against dengue virus E protein peptide bind to human plasminogen and inhibit plasmin activity. Clin Exp Immunol. 1997;110:35-40.

  97. Chuang YC, Lei HY, Lin YS, Liu HS, Wu HL, Yeh TM. Dengue virus-induced autoantibodies bind to plasminogen and enhance its activation. J Immunol. 2011;187:6483-90.

  98. Lin CF, Lei HY, Shiau AL, et al. Antibodies from dengue patient sera cross-react with endothelial cells and induce damage. J Med Virol. 2003;69:82-90.

  99. Guzmán MG, Kourí G, Valdés L, Bravo J, Vázquez S, Halstead SB. Enhanced severity of secondary dengue-2 infections: death rates in 1981 and 1997 Cuban outbreaks. Rev Panam Salud Publica. 2002; 11:223-7.

  100. Fried JR, Gibbons RV, Kalayanarooj S, et al. Serotype-specific differences in the risk of dengue hemorrhagic fever: an analysis of data collected in Bangkok, Thailand from 1994 to 2006. PLoS Negl Trop Dis. 2010;4:e617.

>Journals >Gaceta Médica de México >Year 2013, Issue 5

· Journal Index 
· Links 

Copyright 2019