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Progress towards understanding the pathogenesis of dengue hemorrhagic fever

Virologica Sinica volume 32, pages16–22(2017)Cite this article

Abstract

Dengue virus (DENV) is a mosquito-borne virus belonging to the Flaviviridae family. There are 4 serotypes of DENV that cause human disease through transmission by mosquito vectors. DENV infection results in a broad spectrum of clinical symptoms, ranging from mild fever to dengue hemorrhagic fever (DHF), the latter of which can progress to dengue shock syndrome (DSS) and death. Researchers have made unremitting efforts over the last half-century to understand DHF pathogenesis. DHF is probably caused by multiple factors, such as virus-specific antibodies, viral antigens and host immune responses. This review summarizes the current progress of studies on DHF pathogenesis, which may provide important information for achieving effective control of dengue in the future.

References

  1. Alvarez M, Rodriguez-Roche R, Bernardo L, Vazquez S, Morier L, Gonzalez D, Castro O, Kouri G, Halstead SB, Guzman MG. 2006. Dengue hemorrhagic Fever caused by sequential dengue 1-3 virus infections over a long time interval: Havana epidemic, 2001-2002. Am J Trop Med Hyg, 75: 1113–1117.

    PubMed  Google Scholar 

  2. Anderson JR, Rico-Hesse R. 2006. Aedes aegypti vectorial capacity is determined by the infecting genotype of dengue virus. Am J Trop Med Hyg, 75: 886–892.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Avirutnan P, Zhang L, Punyadee N, Manuyakorn A, Puttikhunt C, Kasinrerk W, Malasit P, Atkinson JP, Diamond MS. 2007. Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E. PLoS Pathog, 3: e183.

    PubMed  PubMed Central  Google Scholar 

  4. Beatty PR, Puerta-Guardo H, Killingbeck SS, Glasner DR, Hopkins K, Harris E. 2015. Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination. Sci Transl Med, 7: 304ra141.

    Google Scholar 

  5. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI. 2013. The global distribution and burden of dengue. Nature, 496: 504–507.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Bozza FA, Cruz OG, Zagne SM, Azeredo EL, Nogueira RM, Assis EF, Bozza PT, Kubelka CF. 2008. Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity. BMC Infect Dis, 8: 86.

    PubMed  PubMed Central  Google Scholar 

  7. Brown MG, Hermann LL, Issekutz AC, Marshall JS, Rowter D, Al-Afif A, Anderson R. 2011. Dengue virus infection of mast cells triggers endothelial cell activation. J Virol, 85: 1145–1150.

    CAS  PubMed  Google Scholar 

  8. Chaichana P, Okabayashi T, Puiprom O, Sasayama M, Sasaki T, Yamashita A, Ramasoota P, Kurosu T, Ikuta K. 2014. Low levels of antibody-dependent enhancement in vitro using viruses and plasma from dengue patients. PLoS One, 9: e92173.

    PubMed  PubMed Central  Google Scholar 

  9. Chan-Hui PY, Swiderek KM. 2016. Immunological considerations for developing antibody therapeutics for Influenza A. Hum Vaccin Immunother, 12: 474–477.

    PubMed  Google Scholar 

  10. Chang RY, Hsu TW, Chen YL, Liu SF, Tsai YJ, Lin YT, Chen YS, Fan YH. 2013. Japanese encephalitis virus non-coding RNA inhibits activation of interferon by blocking nuclear translocation of interferon regulatory factor 3. Vet Microbiol, 166: 11–21.

    CAS  PubMed  Google Scholar 

  11. Chapman EG, Costantino DA, Rabe JL, Moon SL, Wilusz J, Nix JC, Kieft JS. 2014. The structural basis of pathogenic subgenomic flavivirus RNA (sfRNA) production. Science, 344: 307–310.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen HL, Lin SR, Liu HF, King CC, Hsieh SC, Wang WK. 2008. Evolution of dengue virus type 2 during two consecutive outbreaks with an increase in severity in southern Taiwan in 2001–2002. Am J Trop Med Hyg, 79: 495–505.

    CAS  PubMed  Google Scholar 

  13. Chen HR, Chuang YC, Lin YS, Liu HS, Liu CC, Perng GC, Yeh TM. 2016. Dengue Virus Nonstructural Protein 1 Induces Vascular Leakage through Macrophage Migration Inhibitory Factor and Autophagy. PLoS Negl Trop Dis, 10: e0004828.

    PubMed  PubMed Central  Google Scholar 

  14. Chuang YC, Lin J, Lin YS, Wang S, Yeh TM. 2016. Dengue Virus Nonstructural Protein 1-Induced Antibodies Cross-React with Human Plasminogen and Enhance Its Activation. J Immunol, 196: 1218–1226.

    CAS  PubMed  Google Scholar 

  15. Chuang YC, Wang SY, Lin YS, Chen HR, Yeh TM. 2013. Reevaluation of the pathogenic roles of nonstructural protein 1 and its antibodies during dengue virus infection. J Biomed Sci, 20: 42.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, Limpitikul W, Puttikhunt C, Edwards C, Duangchinda T, Supasa S, Chawansuntati K, Malasit P, Mongkolsapaya J, Screaton G. 2010. Cross-reacting antibodies enhance dengue virus infection in humans. Science, 328: 745–748.

    CAS  PubMed  Google Scholar 

  17. Falconar AK. 1997. The dengue virus nonstructural-1 protein (NS1) generates antibodies to common epitopes on human blood clotting, integrin/adhesin proteins and binds to human endothelial cells: potential implications in haemorrhagic fever pathogenesis. Arch Virol, 142: 897–916.

    CAS  PubMed  Google Scholar 

  18. Funk A, Truong K, Nagasaki T, Torres S, Floden N, Balmori Melian E, Edmonds J, Dong H, Shi PY, Khromykh AA. 2010. RNA structures required for production of subgenomic flavivirus RNA. J Virol, 84: 11407–11417.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Goncalvez AP, Engle RE, St Claire M, Purcell RH, Lai CJ. 2007. Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention. Proc Natl Acad Sci U S A, 104: 9422–9427.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. Gubler DJ. 2011. Emerging vector-borne flavivirus diseases: are vaccines the solution? Expert Rev Vaccines, 10: 563–565.

    PubMed  Google Scholar 

  22. Gubler DJ, Suharyono W, Lubis I, Eram S, Gunarso S. 1981. Epidemic dengue 3 in central Java, associated with low viremia in man. Am J Trop Med Hyg, 30: 1094–1099.

    CAS  PubMed  Google Scholar 

  23. Guzman MG, Alvarez M, Halstead SB. 2013. Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection. Arch Virol, 158: 1445–1459.

    CAS  PubMed  Google Scholar 

  24. Guzman MG, Kouri G, Halstead SB. 2000. Do escape mutants explain rapid increases in dengue case-fatality rates within epidemics? Lancet, 355: 1902–1903.

    CAS  PubMed  Google Scholar 

  25. Halstead SB. 1970. Observations related to pathogensis of dengue hemorrhagic fever. VI. Hypotheses and discussion. Yale J Biol Med, 42: 350–362.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Halstead SB. 1982. Immune enhancement of viral infection. Prog Allergy, 31: 301–364.

    CAS  PubMed  Google Scholar 

  27. Halstead SB, Cohen SN. 2015. Dengue Hemorrhagic Fever at 60 Years: Early Evolution of Concepts of Causation and Treatment. Microbiol Mol Biol Rev, 79: 281–291.

    PubMed  PubMed Central  Google Scholar 

  28. Halstead SB, Lan NT, Myint TT, Shwe TN, Nisalak A, Kalyanarooj S, Nimmannitya S, Soegijanto S, Vaughn DW, Endy TP. 2002. Dengue hemorrhagic fever in infants: research opportunities ignored. Emerg Infect Dis, 8: 1474–1479.

    PubMed  PubMed Central  Google Scholar 

  29. Hermann LL, Gupta SB, Manoff SB, Kalayanarooj S, Gibbons RV, Coller BA. 2015. Advances in the understanding, management, and prevention of dengue. J Clin Virol, 64: 153–159.

    PubMed  Google Scholar 

  30. Hladish TJ, Pearson CA, Chao DL, Rojas DP, Recchia GL, Gomez-Dantes H, Halloran ME, Pulliam JR, Longini IM. 2016. Projected Impact of Dengue Vaccination in Yucatan, Mexico. PLoS Negl Trop Dis, 10: e0004661.

    PubMed  PubMed Central  Google Scholar 

  31. Jacobs MG, Robinson PJ, Bletchly C, Mackenzie JM, Young PR. 2000. Dengue virus nonstructural protein 1 is expressed in a glycosyl-phosphatidylinositol-linked form that is capable of signal transduction. FASEB J, 14: 1603–1610.

    CAS  PubMed  Google Scholar 

  32. Jaiyen Y, Masrinoul P, Kalayanarooj S, Pulmanausahakul R, Ubol S. 2009. Characteristics of dengue virus-infected peripheral blood mononuclear cell death that correlates with the severity of illness. Microbiol Immunol, 53: 442–450.

    CAS  PubMed  Google Scholar 

  33. King CA, Anderson R, Marshall JS. 2002. Dengue virus selectively induces human mast cell chemokine production. J Virol, 76: 8408–8419.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kurane I, Matsutani T, Suzuki R, Takasaki T, Kalayanarooj S, Green S, Rothman AL, Ennis FA. 2011. T-cell responses to dengue virus in humans. Trop Med Health, 39: 45–51.

    PubMed  PubMed Central  Google Scholar 

  35. Kurosu T, Chaichana P, Yamate M, Anantapreecha S, Ikuta K. 2007. Secreted complement regulatory protein clusterin interacts with dengue virus nonstructural protein 1. Biochem Biophys Res Commun, 362: 1051–1056.

    CAS  PubMed  Google Scholar 

  36. Libraty DH, Young PR, Pickering D, Endy TP, Kalayanarooj S, Green S, Vaughn DW, Nisalak A, Ennis FA, Rothman AL. 2002. High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis, 186: 1165–1168.

    CAS  PubMed  Google Scholar 

  37. Lin CF, Chiu SC, Hsiao YL, Wan SW, Lei HY, Shiau AL, Liu HS, Yeh TM, Chen SH, Liu CC, Lin YS. 2005. Expression of cytokine, chemokine, and adhesion molecules during endothelial cell activation induced by antibodies against dengue virus nonstructural protein 1. J Immunol, 174: 395–403.

    CAS  PubMed  Google Scholar 

  38. Liu JY, Liu Y, Nie KX, Du SY, Pang XJ, Wang PH, Cheng G. 2016. Flavivirus acquisition by mosquitoes requires the secretion of nonstructural protein 1 from infected hosts. Nature Microbiology. 1: 16087.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Luo YY, Feng JJ, Zhou JM, Yu ZZ, Fang DY, Yan HJ, Zeng GC, Jiang LF. 2013. Identification of a novel infection-enhancing epitope on dengue prM using a dengue cross-reacting monoclonal antibody. BMC Microbiol, 13: 194.

    PubMed  PubMed Central  Google Scholar 

  40. Malavige GN, Huang LC, Salimi M, Gomes L, Jayaratne SD, Ogg GS. 2012. Cellular and cytokine correlates of severe dengue infection. PLoS One, 7: e50387.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Mammen MP, Lyons A, Innis BL, Sun W, McKinney D, Chung RC, Eckels KH, Putnak R, Kanesa-thasan N, Scherer JM, Statler J, Asher LV, Thomas SJ, Vaughn DW. 2014. Evaluation of dengue virus strains for human challenge studies. Vaccine, 32: 1488–1494.

    CAS  PubMed  Google Scholar 

  42. Manokaran G, Finol E, Wang C, Gunaratne J, Bahl J, Ong EZ, Tan HC, Sessions OM, Ward AM, Gubler DJ, Harris E, Garcia-Blanco MA, Ooi EE. 2015. Dengue subgenomic RNA binds TRIM25 to inhibit interferon expression for epidemiological fitness. Science, 350: 217–221.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Martina BE, Koraka P, Osterhaus AD. 2009. Dengue virus pathogenesis: an integrated view. Clin Microbiol Rev, 22: 564–581.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Martinez Gomez JM, Ong LC, Lam JH, Binte Aman SA, Libau EA, Lee PX, St John AL, Alonso S. 2016. Maternal Antibody-Mediated Disease Enhancement in Type I Interferon-Deficient Mice Leads to Lethal Disease Associated with Liver Damage. PLoS Negl Trop Dis, 10: e0004536.

    PubMed  PubMed Central  Google Scholar 

  45. Mathew A, Rothman AL. 2008. Understanding the contribution of cellular immunity to dengue disease pathogenesis. Immunol Rev, 225: 300–313.

    CAS  PubMed  Google Scholar 

  46. Midgley CM, Bajwa-Joseph M, Vasanawathana S, Limpitikul W, Wills B, Flanagan A, Waiyaiya E, Tran HB, Cowper AE, Chotiyarnwong P, Grimes JM, Yoksan S, Malasit P, Simmons CP, Mongkolsapaya J, Screaton GR. 2011. An in-depth analysis of original antigenic sin in dengue virus infection. J Virol, 85: 410–421.

    CAS  PubMed  Google Scholar 

  47. Modhiran N, Watterson D, Muller DA, Panetta AK, Sester DP, Liu L, Hume DA, Stacey KJ, Young PR. 2015. Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity. Sci Transl Med, 7: 304ra142.

    PubMed  Google Scholar 

  48. Moon SL, Anderson JR, Kumagai Y, Wilusz CJ, Akira S, Khromykh AA, Wilusz J. 2012. A noncoding RNA produced by arthropod-borne flaviviruses inhibits the cellular exoribonuclease XRN1 and alters host mRNA stability. RNA, 18: 2029–2040.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Nielsen DG. 2009. The relationship of interacting immunological components in dengue pathogenesis. Virol J, 6: 211.

    PubMed  PubMed Central  Google Scholar 

  50. Pijlman GP, Funk A, Kondratieva N, Leung J, Torres S, van der Aa L, Liu WJ, Palmenberg AC, Shi PY, Hall RA, Khromykh AA. 2008. A highly structured, nuclease-resistant, noncoding RNA produced by flaviviruses is required for pathogenicity. Cell Host Microbe, 4: 579–591.

    CAS  PubMed  Google Scholar 

  51. Rachman A, Harahap AR, Widhyasih RM. 2013. The role of antidengue virus NS-1 and anti-protein disulfide isomerase antibodies on platelet aggregation in secondary dengue infection. Acta Med Indones, 45: 44–48.

    PubMed  Google Scholar 

  52. Recker M, Vannice K, Hombach J, Jit M, Simmons CP. 2016. Assessing dengue vaccination impact: Model challenges and future directions. Vaccine, 34: 4461–4465.

    PubMed  Google Scholar 

  53. Rico-Hesse R, Harrison LM, Nisalak A, Vaughn DW, Kalayanarooj S, Green S, Rothman AL, Ennis FA. 1998. Molecular evolution of dengue type 2 virus in Thailand. Am J Trop Med Hyg, 58: 96–101.

    CAS  PubMed  Google Scholar 

  54. Rico-Hesse R, Harrison LM, Salas RA, Tovar D, Nisalak A, Ramos C, Boshell J, de Mesa MT, Nogueira RM, da Rosa AT. 1997. Origins of dengue type 2 viruses associated with increased pathogenicity in the Americas. Virology, 230: 244–251.

    CAS  PubMed  Google Scholar 

  55. Ritchie SA, Pyke AT, Hall-Mendelin S, Day A, Mores CN, Christofferson RC, Gubler DJ, Bennett SN, van den Hurk AF. 2013. An explosive epidemic of DENV-3 in Cairns, Australia. PLoS One, 8: e68137.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Roby JA, Pijlman GP, Wilusz J, Khromykh AA. 2014. Noncoding subgenomic flavivirus RNA: multiple functions in West Nile virus pathogenesis and modulation of host responses. Viruses, 6: 404–427.

    PubMed  PubMed Central  Google Scholar 

  57. Sabchareon A, Wallace D, Sirivichayakul C, Limkittikul K, Chanthavanich P, Suvannadabba S, Jiwariyavej V, Dulyachai W, Pengsaa K, Wartel TA, Moureau A, Saville M, Bouckenooghe A, Viviani S, Tornieporth NG, Lang J. 2012. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet, 380: 1559–1567.

    CAS  PubMed  Google Scholar 

  58. Sasaki T, Setthapramote C, Kurosu T, Nishimura M, Asai A, Omokoko MD, Pipattanaboon C, Pitaksajjakul P, Limkittikul K, Subchareon A, Chaichana P, Okabayashi T, Hirai I, Leaungwutiwong P, Misaki R, Fujiyama K, Ono K, Okuno Y, Ramasoota P, Ikuta K. 2013. Dengue virus neutralization and antibody-dependent enhancement activities of human monoclonal antibodies derived from dengue patients at acute phase of secondary infection. Antiviral Res, 98: 423–431.

    CAS  PubMed  Google Scholar 

  59. Sato R, Hamada N, Kashiwagi T, Imamura Y, Hara K, Nishimura M, Kamimura T, Takasaki T, Watanabe H, Koga T. 2015. Dengue Hemorrhagic Fever in a Japanese Traveler with Preexisting Japanese Encephalitis Virus Antibody. Trop Med Health, 43: 85–88.

    PubMed  PubMed Central  Google Scholar 

  60. Schnettler E, Sterken MG, Leung JY, Metz SW, Geertsema C, Goldbach RW, Vlak JM, Kohl A, Khromykh AA, Pijlman GP. 2012. Noncoding flavivirus RNA displays RNA interference suppressor activity in insect and Mammalian cells. J Virol, 86: 13486–13500.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Smith SA, Zhou Y, Olivarez NP, Broadwater AH, de Silva AM, Crowe JE, Jr. 2012. Persistence of circulating memory B cell clones with potential for dengue virus disease enhancement for decades following infection. J Virol, 86: 2665–2675.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Srikiatkhachorn A. 2009. Plasma leakage in dengue haemorrhagic fever. Thromb Haemost, 102: 1042–1049.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Srikiatkhachorn A, Kelley JF. 2014. Endothelial cells in dengue hemorrhagic fever. Antiviral Res, 109: 160–170.

    CAS  PubMed  Google Scholar 

  64. Sun DS, King CC, Huang HS, Shih YL, Lee CC, Tsai WJ, Yu CC, Chang HH. 2007. Antiplatelet autoantibodies elicited by dengue virus non-structural protein 1 cause thrombocytopenia and mortality in mice. J Thromb Haemost, 5: 2291–2299.

    CAS  PubMed  Google Scholar 

  65. Suresh R, Chandrasekaran P, Sutterwala FS, Mosser DM. 2016. Complement-mediated ‘bystander’ damage initiates host NLRP3 inflammasome activation. J Cell Sci, 129: 1928–1939.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Takada A, Feldmann H, Ksiazek TG, Kawaoka Y. 2003. Antibody-dependent enhancement of Ebola virus infection. J Virol, 77: 7539–7544.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Ubol S, Chareonsirisuthigul T, Kasisith J, Klungthong C. 2008. Clinical isolates of dengue virus with distinctive susceptibility to nitric oxide radical induce differential gene responses in THP-1 cells. Virology, 376: 290–296.

    CAS  PubMed  Google Scholar 

  68. Ubol S, Halstead SB. 2010. How innate immune mechanisms contribute to antibody-enhanced viral infections. Clin Vaccine Immunol, 17: 1829–1835.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Vasilakis N, Shell EJ, Fokam EB, Mason PW, Hanley KA, Estes DM, Weaver SC. 2007. Potential of ancestral sylvatic dengue-2 viruses to re-emerge. Virology, 358: 402–412.

    CAS  PubMed  Google Scholar 

  70. Wan SW, Lu YT, Huang CH, Lin CF, Anderson R, Liu HS, Yeh TM, Yen YT, Wu-Hsieh BA, Lin YS. 2014. Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1. PLoS One, 9: e92495.

    PubMed  PubMed Central  Google Scholar 

  71. WHO/TDR. 2009. Dengue guidelines for diagnosis, treatment, prevention and control. New Edition. WHO Press, Geneva.

    Google Scholar 

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Affiliations

  1. Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China

    Xiaojing Pang, Rudian Zhang & Gong Cheng

  2. School of Life Science, Tsinghua University, Beijing, 100084, China

    Rudian Zhang & Gong Cheng

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  1. Xiaojing Pang
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  2. Rudian Zhang
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  3. Gong Cheng
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Correspondence to Gong Cheng.

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Pang, X., Zhang, R. & Cheng, G. Progress towards understanding the pathogenesis of dengue hemorrhagic fever. Virol. Sin. 32, 16–22 (2017). https://doi.org/10.1007/s12250-016-3855-9

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Keywords

  • DENV
  • dengue hemorrhagic fever (DHF)
  • NS1
  • genome
  • antibody-dependent enhancement (ADE)
  • T cell