1887

Abstract

The depletion of -tryptophan (L-Trp) has been associated with the inhibition of growth of micro-organisms and also has profound effects on T cell proliferation and immune tolerance. The enzyme indoleamine 2,3-dioxygenase (IDO) catalyses the rate-limiting step in the catabolic pathway of L-Trp. Gene expression analysis has shown upregulation of genes involved in L-Trp catabolism in models of dengue virus (DENV) infection. To understand the role of IDO during DENV infection, we measured IDO activity in sera from control and DENV-infected patients. We found increased IDO activity, lower levels of L-Trp and higher levels of -kynurenine in sera from DENV-infected patients during the febrile days of the disease compared with patients with other febrile illnesses and healthy donors. Furthermore, we confirmed upregulation of IDO mRNA expression in response to DENV infection , using a dendritic cell (DC) model of DENV infection. We found that the antiviral effect of gamma interferon (IFN-) in DENV-infected DCs was partially dependent on IDO activity. Our results demonstrate that IDO plays an important role in the antiviral effect of IFN- against DENV infection and suggest that it has a role in the immune response to DENV infections .

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.004416-0
2009-04-01
2019-11-12
Loading full text...

Full text loading...

/deliver/fulltext/jgv/90/4/810.html?itemId=/content/journal/jgv/10.1099/vir.0.004416-0&mimeType=html&fmt=ahah

References

  1. Adams, O., Besken, K., Oberdörfer, C., MacKenzie, C. R., Takikawa, O. & Däubener, W. ( 2004; ). Role of indoleamine-2,3-dioxygenase in alpha/beta and gamma interferon-mediated antiviral effects against herpes simplex virus infections. J Virol 78, 2632–2636.[CrossRef]
    [Google Scholar]
  2. Becerra, A., Warke, R. V., de Bosch, N., Rothman, A. L. & Bosch, I. ( 2008; ). Elevated levels of soluble ST2 protein in dengue virus infected patients. Cytokine 41, 114–120.[CrossRef]
    [Google Scholar]
  3. Bodaghi, B., Goureau, O., Zipeto, D., Laurent, L., Virelizier, J. L. & Michelson, S. ( 1999; ). Role of IFN-γ-induced indoleamine 2,3 dioxygenase and inducible nitric oxide synthase in the replication of human cytomegalovirus in retinal pigment epithelial cells. J Immunol 162, 957–964.
    [Google Scholar]
  4. Cady, S. G. & Sono, M. ( 1991; ). 1-Methyl-dl-tryptophan, β-(3-benzofuranyl)-dl-alanine (the oxygen analog of tryptophan), and β-[3-benzo(b)thienyl]-dl-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. Arch Biochem Biophys 291, 326–333.[CrossRef]
    [Google Scholar]
  5. Carlin, J. M., Ozaki, Y., Byrne, G. I., Brown, R. R. & Borden, E. C. ( 1989; ). Interferons and indoleamine 2,3-dioxygenase: role in antimicrobial and antitumor effects. Experientia 45, 535–541.[CrossRef]
    [Google Scholar]
  6. Chaturvedi, U. C., Agarwal, R., Elbishbishi, E. A. & Mustafa, A. S. ( 2000; ). Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis. FEMS Immunol Med Microbiol 28, 183–188.[CrossRef]
    [Google Scholar]
  7. Chaturvedi, U., Nagar, R. & Shrivastava, R. ( 2006; ). Dengue and dengue haemorrhagic fever: implications of host genetics. FEMS Immunol Med Microbiol 47, 155–166.[CrossRef]
    [Google Scholar]
  8. Fallarino, F., Grohmann, U., You, S., McGrath, B. C., Cavener, D. R., Vacca, C., Orabona, C., Bianchi, R., Belladonna, M. L. & other authors ( 2006; ). The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176, 6752–6761.[CrossRef]
    [Google Scholar]
  9. Hassanain, H. H., Chon, S. Y. & Gupta, S. L. ( 1993; ). Differential regulation of human indoleamine 2,3-dioxygenase gene expression by interferons-γ and -α. Analysis of the regulatory region of the gene and identification of an interferon-gamma-inducible DNA-binding factor. J Biol Chem 268, 5077–5084.
    [Google Scholar]
  10. Heseler, K., Spekker, K., Schmidt, S. K., Mackenzie, C. R. & Daubener, W. ( 2008; ). Antimicrobial and immunoregulatory effects mediated by human lung cells: role of IFN-γ-induced tryptophan degradation. FEMS Immunol Med Microbiol 52, 273–281.[CrossRef]
    [Google Scholar]
  11. Ho, L. J., Hung, L. F., Weng, C. Y., Wu, W. L., Chou, P., Lin, Y. L., Chang, D. M., Tai, T. Y. & Lai, J. H. ( 2005; ). Dengue virus type 2 antagonizes IFN-α but not IFN-γ antiviral effect via down-regulating Tyk2-STAT signaling in the human dendritic cell. J Immunol 174, 8163–8172.[CrossRef]
    [Google Scholar]
  12. Jones, M., Davidson, A., Hibbert, L., Gruenwald, P., Schlaak, J., Ball, S., Foster, G. R. & Jacobs, M. ( 2005; ). Dengue virus inhibits alpha interferon signaling by reducing STAT2 expression. J Virol 79, 5414–5420.[CrossRef]
    [Google Scholar]
  13. King, N. J. & Thomas, S. R. ( 2007; ). Molecules in focus: indoleamine 2,3-dioxygenase. Int J Biochem Cell Biol 39, 2167–2172.[CrossRef]
    [Google Scholar]
  14. Kujundzić, R. N. & Lowenthal, J. W. ( 2008; ). The role of tryptophan metabolism in iNOS transcription and nitric oxide production by chicken macrophage cells upon treatment with interferon gamma. Immunol Lett 115, 153–159.[CrossRef]
    [Google Scholar]
  15. Libraty, D. H., Pichyangkul, S., Ajariyakhajorn, C., Endy, T. P. & Ennis, F. A. ( 2001; ). Human dendritic cells are activated by dengue virus infection: enhancement by gamma interferon and implications for disease pathogenesis. J Virol 75, 3501–3508.[CrossRef]
    [Google Scholar]
  16. Libraty, D. H., Endy, T. P., Houng, H. S., Green, S., Kalayanarooj, S., Suntayakorn, S., Chansiriwongs, W., Vaughn, D. W., Nisalak, A. & other authors ( 2002; ). Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections. J Infect Dis 185, 1213–1221.[CrossRef]
    [Google Scholar]
  17. Livak, K. J. & Schmittgen, T. D. ( 2001; ). Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔC t Method. Methods 25, 402–408.[CrossRef]
    [Google Scholar]
  18. MacKenzie, C. R., Hucke, C., Müller, D., Seidel, K., Takikawa, O. & Däubener, W. ( 1999; ). Growth inhibition of multiresistant enterococci by interferon-γ-activated human uro-epithelial cells. J Med Microbiol 48, 935–941.[CrossRef]
    [Google Scholar]
  19. MacKenzie, C. R., Heseler, K., Müller, A. & Däubener, W. ( 2007; ). Role of indoleamine 2,3-dioxygenase in antimicrobial defence and immuno-regulation: tryptophan depletion versus production of toxic kynurenines. Curr Drug Metab 8, 237–244.[CrossRef]
    [Google Scholar]
  20. Mellor, A. L. & Munn, D. H. ( 2004; ). IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4, 762–774.[CrossRef]
    [Google Scholar]
  21. Monath, T. P. ( 1994; ). Dengue: the risk to developed and developing countries. Proc Natl Acad Sci U S A 91, 2395–2400.[CrossRef]
    [Google Scholar]
  22. Neves-Souza, P. C., Azeredo, E. L., Zagne, S. M., Valls-de-Souza, R., Reis, S. R., Cerqueira, D. I., Nogueira, R. M. & Kubelka, C. F. ( 2005; ). Inducible nitric oxide synthase (iNOS) expression in monocytes during acute Dengue Fever in patients and during in vitro infection. BMC Infect Dis 5, 64 [CrossRef]
    [Google Scholar]
  23. Puccetti, P. ( 2007; ). On watching the watchers: IDO and type I/II IFN. Eur J Immunol 37, 876–879.[CrossRef]
    [Google Scholar]
  24. Rapoza, P. A., Tahija, S. G., Carlin, J. P., Miller, S. L., Padilla, M. L. & Byrne, G. I. ( 1991; ). Effect of interferon on a primary conjunctival epithelial cell model of trachoma. Invest Ophthalmol Vis Sci 32, 2919–2923.
    [Google Scholar]
  25. Rothman, A. L. & Ennis, F. A. ( 1999; ). Immunopathogenesis of Dengue hemorrhagic fever. Virology 257, 1–6.[CrossRef]
    [Google Scholar]
  26. Schroten, H., Spors, B., Hucke, C., Stins, M., Kim, K. S., Adam, R. & Däubener, W. ( 2001; ). Potential role of human brain microvascular endothelial cells in the pathogenesis of brain abscess: inhibition of Staphylococcus aureus by activation of indoleamine 2,3-dioxygenase. Neuropediatrics 32, 206–210.[CrossRef]
    [Google Scholar]
  27. Sekkai, D., Guittet, O., Lemaire, G., Tenu, J. P. & Lepoivre, M. ( 1997; ). Inhibition of nitric oxide synthase expression and activity in macrophages by 3-hydroxyanthranilic acid, a tryptophan metabolite. Arch Biochem Biophys 340, 117–123.[CrossRef]
    [Google Scholar]
  28. Terajima, M. & Leporati, A. M. ( 2005; ). Role of indoleamine 2,3-dioxygenase in antiviral activity of interferon-γ against vaccinia virus. Viral Immunol 18, 722–729.[CrossRef]
    [Google Scholar]
  29. Thomas, S. M., Garrity, L. F., Brandt, C. R., Schobert, C. S., Feng, G. S., Taylor, M. W., Carlin, J. M. & Byrne, G. I. ( 1993; ). IFN-gamma-mediated antimicrobial response. Indoleamine 2,3-dioxygenase-deficient mutant host cells no longer inhibit intracellular Chlamydia spp. or Toxoplasma growth. J Immunol 150, 5529–5534.
    [Google Scholar]
  30. Thomas, S. R., Terentis, A. C., Cai, H., Takikawa, O., Levina, A., Lay, P. A., Freewan, M. & Stocker, R. ( 2007; ). Post-translational regulation of human indoleamine 2,3-dioxygenase activity by nitric oxide. J Biol Chem 282, 23778–23787.[CrossRef]
    [Google Scholar]
  31. Valero, N., Espina, L. M., Anez, G., Torres, E. & Mosquera, J. A. ( 2002; ). Short report: increased level of serum nitric oxide in patients with dengue. Am J Trop Med Hyg 66, 762–764.
    [Google Scholar]
  32. WHO ( 2003; ). Joint WHO HQ/SEAROP/WPRO meeting on DengueNet implementation in South-East Asia and the Western Pacific, Kuala Lumpur, 11–13 December 2003. Wkly Epidemiol Rec 78, 346–347.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.004416-0
Loading
/content/journal/jgv/10.1099/vir.0.004416-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error