Volume 88, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Dengue hemorrhagic fever is characterized by a unique vascular leakage syndrome. The mechanisms of endothelial barrier dysfunction in dengue hemorrhagic fever are not well understood. We examined the modulation of endothelial barrier function in dengue virus type 2 (DENV2) infections using primary human umbilical vein endothelial cells. We demonstrated that the increase in endothelial barrier function within 72 hours after DENV2 infection is mediated by type I interferon–dependent CD73 up-regulation. After 72 hours, DENV2 slowed the recovery of endothelial barrier function in response to tumor necrosis factor-α or vascular endothelial growth factor. This phenomenon was likely caused by type I interferon receptor signaling inhibition and lower CD73 levels in DENV2-infected endothelial cells. Our findings suggest that during DENV2 infection, endothelial barrier homeostasis is maintained by a balance between pro-inflammatory and pro-angiogenic cytokines, and type I interferon–dependent CD73 expression and activity.

[open-access] This is an Open Access article distributed under the terms of the American Society of Tropical Medicine and Hygiene's Re-use License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


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  1. Initiative DV, , 2012. Disease Burden. Available at: http://www.denguevaccines.org/disease-burden. Accessed May 7, 2012. [Google Scholar]
  2. Henchal EA, Putnak JR, , 1990. The dengue viruses. Clin Microbiol Rev 3: 376396.[Crossref] [Google Scholar]
  3. Dewi BE, Takasaki T, Kurane I, , 2004. In vitro assessment of human endothelial cell permeability: effects of inflammatory cytokines and dengue virus infection. J Virol Methods 121: 171180.[Crossref] [Google Scholar]
  4. Talavera D, Castillo AM, Dominguez MC, Gutierrez AE, Meza I, , 2004. IL8 release, tight junction and cytoskeleton dynamic reorganization conducive to permeability increase are induced by dengue virus infection of microvascular endothelial monolayers. J Gen Virol 85: 18011813.[Crossref] [Google Scholar]
  5. Jessie K, Fong MY, Devi S, Lam SK, Wong KT, , 2004. Localization of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ hybridization. J Infect Dis 189: 14111418.[Crossref] [Google Scholar]
  6. Gubler DJ, Zaki SR, Nelson AM, Horsburgh CR, Jr, 1998. Dengue and other viral hemorrhagic fevers. , eds. Pathology of Emerging Infections 2. Washington, DC: American Society for Microbiology Press, 4367. [Google Scholar]
  7. Rothman AL, , 2011. Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat Rev Immunol 11: 532543.[Crossref] [Google Scholar]
  8. World Health Oganization, 1997. Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control. Geneva: World Health Organization. [Google Scholar]
  9. Rothman AL, Ennis FA, , 1999. Immunopathogenesis of dengue hemorrhagic fever. Virology 257: 16.[Crossref] [Google Scholar]
  10. Mehta D, Malik AB, , 2006. Signaling mechanisms regulating endothelial permeability. Physiol Rev 86: 279367.[Crossref] [Google Scholar]
  11. Shasby DM, Roberts RL, , 1987. Transendothelial transfer of macromolecules in vitro . Fed Proc 46: 25062510. [Google Scholar]
  12. Deli MA, Abraham CS, Kataoka Y, Niwa M, , 2005. Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol 25: 59127.[Crossref] [Google Scholar]
  13. Luplertlop N, Misse D, Bray D, Deleuze V, Gonzalez JP, Leardkamolkarn V, Yssel H, Veas F, , 2006. Dengue-virus-infected dendritic cells trigger vascular leakage through metalloproteinase overproduction. EMBO Rep 7: 11761181.[Crossref] [Google Scholar]
  14. Libraty DH, Pichyangkul S, Ajariyakhajorn C, Endy TP, Ennis FA, , 2001. Human dendritic cells are activated by dengue virus infection: enhancement by gamma interferon and implications for disease pathogenesis. J Virol 75: 35013508.[Crossref] [Google Scholar]
  15. Resta R, Yamashita Y, Thompson LF, , 1998. Ecto-enzyme and signaling functions of lymphocyte CD73. Immunol Rev 161: 95109.[Crossref] [Google Scholar]
  16. Narravula S, Lennon PF, Mueller BU, Colgan SP, , 2000. Regulation of endothelial CD73 by adenosine: paracrine pathway for enhanced endothelial barrier function. J Immunol 165: 52625268.[Crossref] [Google Scholar]
  17. Liu P, Woda M, Ennis FA, Libraty DH, , 2009. Dengue virus infection differentially regulates endothelial barrier function over time through type I interferon effects. J Infect Dis 200: 191201.[Crossref] [Google Scholar]
  18. Loo YM, Fornek J, Crochet N, Bajwa G, Perwitasari O, Martinez-Sobrido L, Akira S, Gill MA, Garcia-Sastre A, Katze MG, Gale M, Jr, 2008. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol 82: 335345.[Crossref] [Google Scholar]
  19. Munoz-Jordan JL, Laurent-Rolle M, Ashour J, Martinez-Sobrido L, Ashok M, Lipkin WI, Garcia-Sastre A, , 2005. Inhibition of alpha/beta interferon signaling by the NS4B protein of flaviviruses. J Virol 79: 80048013.[Crossref] [Google Scholar]
  20. Rodriguez-Madoz JR, Belicha-Villanueva A, Bernal-Rubio D, Ashour J, Ayllon J, Fernandez-Sesma A, , 2010. Inhibition of the type I interferon response in human dendritic cells by dengue virus infection requires a catalytically active NS2B3 complex. J Virol 84: 97609774.[Crossref] [Google Scholar]
  21. Srikiatkhachorn A, Ajariyakhajorn C, Endy TP, Kalayanarooj S, Libraty DH, Green S, Ennis FA, Rothman AL, , 2007. Virus-induced decline in soluble vascular endothelial growth receptor 2 is associated with plasma leakage in dengue hemorrhagic fever. J Virol 81: 15921600.[Crossref] [Google Scholar]
  22. Wang JP, Liu P, Latz E, Golenbock DT, Finberg RW, Libraty DH, , 2006. Flavivirus activation of plasmacytoid dendritic cells delineates key elements of TLR7 signaling beyond endosomal recognition. J Immunol 177: 71147121.[Crossref] [Google Scholar]
  23. Chen ST, Lin YL, Huang MT, Wu MF, Cheng SC, Lei HY, Lee CK, Chiou TW, Wong CH, Hsieh SL, , 2008. CLEC5A is critical for dengue-virus-induced lethal disease. Nature 453: 672676.[Crossref] [Google Scholar]
  24. Endy TP, Nisalak A, Chunsuttitwat S, Vaughn DW, Green S, Ennis FA, Rothman AL, Libraty DH, , 2004. Relationship of preexisting dengue virus (DV) neutralizing antibody levels to viremia and severity of disease in a prospective cohort study of DV infection in Thailand. J Infect Dis 189: 9901000.[Crossref] [Google Scholar]
  25. Nooteboom A, Hendriks T, Otteholler I, van der Linden CJ, , 2000. Permeability characteristics of human endothelial monolayers seeded on different extracellular matrix proteins. Mediators Inflamm 9: 235241.[Crossref] [Google Scholar]
  26. Ribatti D, Nico B, Vacca A, Roncali L, Dammacco F, , 2002. Endothelial cell heterogeneity and organ specificity. J Hematother Stem Cell Res 11: 8190.[Crossref] [Google Scholar]
  27. Renkonen J, Tynninen O, Hayry P, Paavonen T, Renkonen R, , 2002. Glycosylation might provide endothelial zip codes for organ-specific leukocyte traffic into inflammatory sites. Am J Pathol 161: 543550.[Crossref] [Google Scholar]

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  • Received : 03 Aug 2012
  • Accepted : 30 Sep 2012
  • Published online : 09 Jan 2013

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