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Barriers to preclinical investigations of anti-dengue immunity and dengue pathogenesis

Nature Reviews Microbiology volume 11, pages 420–426 (2013)Cite this article

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Abstract

Dengue virus (DENV) is a human pathogen that causes severe and potentially fatal disease in millions of individuals each year. Immune-mediated pathology is thought to underlie many of the complications of DENV infection in humans, but the notable limitations of the available animal models have impeded our knowledge of the interactions between DENV and the immune system. In this Opinion article, we discuss some of the controversies in the field of dengue research relating to the interaction between DENV and the mammalian host. We highlight key barriers hindering our understanding of the molecular pathogenesis of DENV and offer suggestions for the most effective ways in which the role of the immune system in the protection from, and pathology of, DENV infection can be addressed experimentally.

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Figure 1: Dengue virus pathogenesis in humans.
Figure 2: Host responses to cutaneous dengue virus injection.

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References

  1. Gubler, D. J. Dengue, urbanization and globalization: the unholy trinity of the 21st century. Trop. Med. Health 39, 3–11 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Gubler, D. J. Dengue and dengue hemorrhagic fever. Clin. Microbiol. Rev. 11, 480–496 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wilder-Smith, A. et al. DengueTools: innovative tools and strategies for the surveillance and control of dengue. Glob. Health Action 5, 17273 (2012).

    Article  Google Scholar 

  4. Siler, J. F., Hall, M. W. & Hitchens, A. P. Results obtained in the transmission of dengue fever. JAMA 84, 1163–1172 (1925).

    Article  Google Scholar 

  5. Sabin, A. B. Research on dengue during World War II. Am. J. Trop. Med. Hyg. 1, 30–50 (1952).

    Article  CAS  PubMed  Google Scholar 

  6. Aggarwal, A., Chandra, J., Aneja, S., Patwari, A. K. & Dutta, A. K. An epidemic of dengue hemorrhagic fever and dengue shock syndrome in children in Delhi. Indian Pediatr. 35, 727–732 (1998).

    CAS  PubMed  Google Scholar 

  7. Vaughn, D. W. et al. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J. Infect. Dis. 181, 2–9 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Bhamarapravati, N., Tuchinda, P. & Boonyapaknavik, V. Pathology of Thailand haemorrhagic fever: a study of 100 autopsy cases. Ann. Trop. Med. Parasitol. 61, 500–510 (1967).

    Article  CAS  PubMed  Google Scholar 

  9. Zompi, S., Montoya, M., Pohl, M. O., Balmaseda, A. & Harris, E. Dominant cross-reactive B cell response during secondary acute dengue virus infection in humans. PLoS Negl. Trop. Dis. 6, e1568 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Steel, A., Gubler, D. J. & Bennett, S. N. Natural attenuation of dengue virus type-2 after a series of island outbreaks: a retrospective phylogenetic study of events in the South Pacific three decades ago. Virology 405, 505–512 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Messer, W. B., Gubler, D. J., Harris, E., Sivananthan, K. & de Silva, A. M. Emergence and global spread of a dengue serotype 3, subtype III virus. Emerg. Infect. Dis. 9, 800–809 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Vejbaesya, S. et al. TNF and LTA gene, allele, and extended HLA haplotype associations with severe dengue virus infection in ethnic Thais. J. Infect. Dis. 199, 1442–1448 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Chen, R. F. et al. Combination of CTLA-4 and TGFβ1 gene polymorphisms associated with dengue hemorrhagic fever and virus load in a dengue-2 outbreak. Clin. Immunol. 131, 404–409 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. de la, C. S. B., Kouri, G. & Guzman, M. G. Race: a risk factor for dengue hemorrhagic fever. Arch. Virol. 152, 533–542 (2007).

    Article  CAS  Google Scholar 

  15. Wu, S. J. et al. Human skin Langerhans cells are targets of dengue virus infection. Nature Med. 6, 816–820 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. St John, A. L. et al. Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance. Proc. Natl Acad. Sci. USA 108, 9190–9195 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Tassaneetrithep, B. et al. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J. Exp. Med. 197, 823–829 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Miller, J. L. et al. The mannose receptor mediates dengue virus infection of macrophages. PLoS Pathog. 4, e17 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Marchette, N. J. et al. Studies on the pathogenesis of dengue infection in monkeys. 3. Sequential distribution of virus in primary and heterologous infections. J. Infect. Dis. 128, 23–30 (1973).

    Article  CAS  PubMed  Google Scholar 

  20. St John, A. L., Rathore, A. P., Raghavan, B., Ng, M. L. & Abraham, S. N. Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage. eLife (in the press).

  21. Rothman, A. L. Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nature Rev. Immunol. 11, 532–543 (2011).

    Article  CAS  Google Scholar 

  22. Wang, T. et al. IFN-γ-producing γδ T cells help control murine West Nile virus infection. J. Immunol. 171, 2524–2531 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Starnes, T. et al. Cutting edge: IL-17F, a novel cytokine selectively expressed in activated T cells and monocytes, regulates angiogenesis and endothelial cell cytokine production. J. Immunol. 167, 4137–4140 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Tsai, Y. T., Chang, S. Y., Lee, C. N. & Kao, C. L. Human TLR3 recognizes dengue virus and modulates viral replication in vitro. Cell. Microbiol. 11, 604–615 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Loo, Y. M. et al. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J. Virol. 82, 335–345 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Halstead, S. B. Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade. Rev. Infect. Dis. 11 (Suppl. 4), S830–S839 (1989).

    Article  PubMed  Google Scholar 

  27. Halstead, S. B. Dengue. Lancet 370, 1644–1652 (2007).

    Article  PubMed  Google Scholar 

  28. Gubler, D. J. & Zaki, S. in Pathology of Emerging Infections 2 Ch. 3 (eds Nelson, A. M. & Horsburgh, C. R.) 43–71 (American Society for Microbiology Press, 1998).

    Google Scholar 

  29. Zellweger, R. M., Prestwood, T. R. & Shresta, S. Enhanced infection of liver sinusoidal endothelial cells in a mouse model of antibody-induced severe dengue disease. Cell Host Microbe 7, 128–139 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jessie, K., Fong, M. Y., Devi, S., Lam, S. K. & Wong, K. T. Localization of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ hybridization. J. Infect. Dis. 189, 1411–1418 (2004).

    Article  PubMed  Google Scholar 

  31. Halstead, S. B. Controversies in dengue pathogenesis. Paediatr. Int. Child Health 32 (Suppl. 1), 5–9 (2012).

    Google Scholar 

  32. Hober, D. et al. Serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in dengue-infected patients. Am. J. Trop. Med. Hyg. 48, 324–331 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Edwards, M. J., Heniford, B. T. & Miller, F. N. Tumor necrosis factor mediates disseminated intravascular inflammation (DII) in the genesis of multiple organ edema. J. Surg. Res. 54, 140–144 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Kunder, C. A., St John, A. L. & Abraham, S. N. Mast cell modulation of the vascular and lymphatic endothelium. Blood 118, 5383–5393 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang, L. et al. Implications of dynamic changes among tumor necrosis factor-α (TNF-α), membrane TNF receptor, and soluble TNF receptor levels in regard to the severity of dengue infection. Am. J. Trop. Med. Hyg. 77, 297–302 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Chakravarti, A. & Kumaria, R. Circulating levels of tumour necrosis factor-α and interferon-γ in patients with dengue and dengue haemorrhagic fever during an outbreak. Indian J. Med. Res. 123, 25–30 (2006).

    CAS  PubMed  Google Scholar 

  37. Halstead, S. B. et al. Dengue hemorrhagic fever in infants: research opportunities ignored. Emerg. Infect. Dis. 8, 1474–1479 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kliks, S. C., Nimmanitya, S., Nisalak, A. & Burke, D. S. Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants. Am. J. Trop. Med. Hyg. 38, 411–419 (1988).

    Article  CAS  PubMed  Google Scholar 

  39. Hawkes, R. A. Enhancement of the infectivity of Arboviruses by specific antisera produced in domestic fowls. Aust. J. Exp. Biol. Med. Sci. 42, 465–482 (1964).

    Article  CAS  PubMed  Google Scholar 

  40. Goncalvez, A. P., Engle, R. E., St Claire, M., Purcell, R. H. & Lai, C. J. Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention. Proc. Natl Acad. Sci. USA 104, 9422–9427 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Daughaday, C. C., Brandt, W. E., McCown, J. M. & Russell, P. K. Evidence for two mechanisms of dengue virus infection of adherent human monocytes: trypsin-sensitive virus receptors and trypsin-resistant immune complex receptors. Infect. Immun. 32, 469–473 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Halstead, S. B., Chow, J. S. & Marchette, N. J. Immunological enhancement of dengue virus replication. Nature New Biol. 243, 24–26 (1973).

    CAS  Google Scholar 

  43. Halstead, S. B. & O'Rourke, E. J. Antibody-enhanced dengue virus infection in primate leukocytes. Nature 265, 739–741 (1977).

    Article  CAS  PubMed  Google Scholar 

  44. Halstead, S. B., Venkateshan, C. N., Gentry, M. K. & Larsen, L. K. Heterogeneity of infection enhancement of dengue 2 strains by monoclonal antibodies. J. Immunol. 132, 1529–1532 (1984).

    CAS  PubMed  Google Scholar 

  45. Webster, R. G. Original antigenic sin in ferrets: the response to sequential infections with influenza viruses. J. Immunol. 97, 177–183 (1966).

    CAS  PubMed  Google Scholar 

  46. Mongkolsapaya, J. et al. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nature Med. 9, 921–927 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Halstead, S. B., Rojanasuphot, S. & Sangkawibha, N. Original antigenic sin in dengue. Am. J. Trop. Med. Hyg. 32, 154–156 (1983).

    Article  CAS  PubMed  Google Scholar 

  48. Singh, R. A., Rodgers, J. R. & Barry, M. A. The role of T cell antagonism and original antigenic sin in genetic immunization. J. Immunol. 169, 6779–6786 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Gubler, D. J., Reed, D., Rosen, L. & Hitchcock, J. R. Jr. Epidemiologic, clinical, and virologic observations on dengue in the Kingdom of Tonga. Am. J. Trop. Med. Hyg. 27, 581–589 (1978).

    Article  CAS  PubMed  Google Scholar 

  50. Vaughn, D. W. et al. Dengue in the early febrile phase: viremia and antibody responses. J. Infect. Dis. 176, 322–330 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Kliks, S. C., Nisalak, A., Brandt, W. E., Wahl, L. & Burke, D. S. Antibody-dependent enhancement of dengue virus growth in human monocytes as a risk factor for dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 40, 444–451 (1989).

    Article  CAS  PubMed  Google Scholar 

  52. Meltzer, E., Heyman, Z., Bin, H. & Schwartz, E. Capillary leakage in travelers with dengue infection: implications for pathogenesis. Am. J. Trop. Med. Hyg. 86, 536–539 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Balsitis, S. J. et al. Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLoS Pathog. 6, e1000790 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shresta, S., Sharar, K. L., Prigozhin, D. M., Beatty, P. R. & Harris, E. Murine model for dengue virus-induced lethal disease with increased vascular permeability. J. Virol. 80, 10208–10217 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. de Borba, L., Strottmann, D. M., de Noronha, L., Mason, P. W. & Dos Santos, C. N. Synergistic interactions between the NS3hel and E proteins contribute to the virulence of dengue virus type 1. PLoS Negl Trop. Dis. 6, e1624 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Avirutnan, P. et al. Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. J. Exp. Med. 207, 793–806 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ashour, J. et al. Mouse STAT2 restricts early dengue virus replication. Cell Host Microbe 8, 410–421 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kochel, T. J. et al. Effect of dengue-1 antibodies on American dengue-2 viral infection and dengue haemorrhagic fever. Lancet 360, 310–312 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Bennett, S. N. et al. Selection-driven evolution of emergent dengue virus. Mol. Biol. Evol. 20, 1650–1658 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Zivna, I. et al. T cell responses to an HLA-B*07-restricted epitope on the dengue NS3 protein correlate with disease severity. J. Immunol. 168, 5959–5965 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Chiewsilp, P., Scott, R. M. & Bhamarapravati, N. Histocompatibility antigens and dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 30, 1100–1105 (1981).

    Article  CAS  PubMed  Google Scholar 

  62. Loke, H. et al. Strong HLA class I–restricted T cell responses in dengue hemorrhagic fever: a double-edged sword? J. Infect. Dis. 184, 1369–1373 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Fernandez-Mestre, M. T., Gendzekhadze, K., Rivas-Vetencourt, P. & Layrisse, Z. TNF-α-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens 64, 469–472 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Soundravally, R. & Hoti, S. L. Polymorphisms of the TAP 1 and 2 gene may influence clinical outcome of primary dengue viral infection. Scand. J. Immunol. 67, 618–625 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Cassetti, M. C. et al. Report of an NIAID workshop on dengue animal models. Vaccine 28, 4229–4234 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Onlamoon, N. et al. Dengue virus-induced hemorrhage in a nonhuman primate model. Blood 115, 1823–1834 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Halstead, S. B., Shotwell, H. & Casals, J. Studies on the pathogenesis of dengue infection in monkeys. I. Clinical laboratory responses to primary infection. J. Infect. Dis. 128, 7–14 (1973).

    Article  CAS  PubMed  Google Scholar 

  68. Omatsu, T. et al. Common marmoset (Callithrix jacchus) as a primate model of dengue virus infection: development of high levels of viraemia and demonstration of protective immunity. J. Gen. Virol. 92, 2272–2280 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Guirakhoo, F. et al. A single amino acid substitution in the envelope protein of chimeric yellow fever-dengue 1 vaccine virus reduces neurovirulence for suckling mice and viremia/viscerotropism for monkeys. J. Virol. 78, 9998–10008 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bente, D. A. & Rico-Hesse, R. Models of dengue virus infection. Drug Discov. Today Dis. Models 3, 97–103 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Yauch, L. E. & Shresta, S. Mouse models of dengue virus infection and disease. Antiviral Res. 80, 87–93 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Simmons, J. S., St. John, J. H., & Reynolds, H. K. Experimental Studies of Dengue (Bureau of Printing, Manila, 1931).

    Google Scholar 

  73. Rathore, A. P. et al. Celgosivir treatment misfolds dengue virus NS1 protein, induces cellular pro-survival genes and protects against lethal challenge mouse model. Antiviral Res. 92, 453–460 (2011).

    CAS  Google Scholar 

  74. Watts, D. M. et al. Failure of secondary infection with American genotype dengue 2 to cause dengue haemorrhagic fever. Lancet 354, 1431–1434 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Thein, S. et al. Risk factors in dengue shock syndrome. Am. J. Trop. Med. Hyg. 56, 566–572 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Vitarana, T., de Silva, H., Withana, N. & Gunasekera, C. Elevated tumour necrosis factor in dengue fever and dengue haemorrhagic fever. Ceylon Med. J. 36, 63–65 (1991).

    CAS  Google Scholar 

  77. Wahala, W. M., Huang, C., Butrapet, S., White, L. J. & de Silva, A. M. Recombinant dengue type 2 viruses with altered e protein domain III epitopes are efficiently neutralized by human immune sera. J. Virol. 86, 4019–4023 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank A. P. S. Rathore for critical reading of the manuscript. This work was supported by the National Medical Research Council of Singapore (grant NIG/1053/2011) and by the Duke-National University of Singapore Signature Research Program, funded by the Ministry of Health, Singapore.

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  1. Ashley L. St. John, Soman N. Abraham and Duane J. Gubler are at the Program in Emerging Infectious Diseases, Graduate Medical School, Duke-National University of Singapore, 8 College Road, 169857, Singapore.,

    Ashley L. St. John, Soman N. Abraham & Duane J. Gubler

  2. Ashley L. St. John and Soman N. Abraham are also at the Department of Pathology, Duke University Medical Center,

    Ashley L. St. John & Soman N. Abraham

  3. Soman N. Abraham is also at the Department of Immunology and the Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA,

    Soman N. Abraham

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St. John, A., Abraham, S. & Gubler, D. Barriers to preclinical investigations of anti-dengue immunity and dengue pathogenesis. Nat Rev Microbiol 11, 420–426 (2013). https://doi.org/10.1038/nrmicro3030

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