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Flaviviruses Induce Pro-inflammatory and Anti-inflammatory Cytokines from Murine Dendritic Cells through MyD88-dependent Pathway

  • Aleyas, Abi G. (Department of Microbiology, College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University) ;
  • George, Junu A. (Department of Microbiology, College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University) ;
  • Han, Young-Woo (Department of Microbiology, College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University) ;
  • Kim, Hye-Kyung (Department of Microbiology, College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University) ;
  • Kim, Seon-Ju (Department of Microbiology, College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University) ;
  • Yoon, Hyun-A (Department of Microbiology, College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University) ;
  • Eo, Seong-Kug (Department of Microbiology, College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University)
  • Published : 2007.06.30
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Abstract

Background: The genus Flavivirus consists of many emerging arboviruses, including Dengue virus (DV), Japanese encephalitis virus (JEV) and West Nile virus (WNV). Effective preventive vaccines remain elusive for these diseases. Mice are being increasingly used as the animal model for vaccine studies. However, the pathogenic mechanisms of these viruses are not clearly understood. Here, we investigated the interaction of DV and JEV with murine bone marrow-derived dendritic cells (bmDC). Methods: ELISA and FACS analysis were employed to investigate cytokine production and phenotypic changes of DCs obtained from bone marrow following flavivirus infection. Results: We observed that these viruses altered the cytokine profile and phenotypic markers. Although both viruses belong to the same family, JEV-infected bmDC produced anti-inflammatory cytokine (IL-10) along with pro-inflammatory cytokines, whereas DV infection induced production of large amounts of pro-inflammatory cytokines (IL-6 and TNF-${\alpha}$) and no IL-10 from murine bmDCs. Both flaviviruses also up-regulated the expression of co-stimulatory molecules such as CD40, CD80 and CD86. JEV infection led to down-regulation of MHC II expression on infected bmDCs. We also found that cytokine production induced by JEV and DV is MyD88-dependent. This dependence was complete for DV, as cytokine production was completely abolished in the absence of MyD88. With regard to JEV, the absence of MyD88 led to a partial reduction in cytokine levels. Conclusion: Here, we demonstrate that MyD88 plays an important role in the pathogenesis of flaviviruses. Our study provides insight into the pathogenesis of JEV and DV in the murine model.

Keywords

References

  1. Rice CM, Lindenbach BD: Flaviviridae. In: Knipe DM, Howley PM, eds.: Fields Virology, Lippincott Williams and Wilkins, Philadelphia, PA, 2001
  2. Schul W, Liu W, Xu HY, Flamand M, Vasudevan SG: A dengue fever viremia model in mice shows reduction in viral replication and suppression of the inflammatory response after treatment with antiviral drugs. J Infect Dis 195;665-674, 2007 https://doi.org/10.1086/511310
  3. Bancahereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 392;245-252, 1998 https://doi.org/10.1038/32588
  4. Wu SJ, Grouard-Vogel G, Sun W, Mascola JR, Brachtel E, Putvatana R, Louder MK, Filgueira L, Marovich MA, Wong HK, Blauvelt A, Murphy GS, Robb ML, Innes BL, Birx DL, Hayes CG, Frankel SS: Human skin Langerhans cells are targets of dengue virus infection. Nat Med 6;816-820, 2000 https://doi.org/10.1038/77553
  5. Ho LJ, Wang JJ, Shaio MF, Kao CL, Chang DM, Han SW, Lai JH: Infection of human dendritic cells by dengue virus causes cell maturation and cytokine production. J Immunol 166;1499-1506, 2001 https://doi.org/10.4049/jimmunol.166.3.1499
  6. Kruse M, Rosorius O, Kratzer F, Stelz G, Kuhnt C, Schuler G, Hauber J, Steinkasserer A: Mature dendritic cells infected with herpes simplex virus type 1 exhibit inhibited T-cell stimulatory capacity. J Virol 74;7127-7136, 2000 https://doi.org/10.1128/JVI.74.15.7127-7136.2000
  7. Moutaftsi M, Mehl AM, Borysiewicz LK, Tabi Z: Human cytomegalovirus inhibits maturation and impairs function of monocyte-derived dendritic cells. Blood 99;2913-2921, 2002 https://doi.org/10.1182/blood.V99.8.2913
  8. Schnorr JJ, Xanthakos S, Keikavoussi P, Kampgen E, ter Meulen V, Schneider-Schaulies S: Induction of maturation of human blood dendritic cell precursors by measles virus is associated with immunosuppression. Proc Natl Acad Sci USA 94;5326-5331, 1997
  9. Palucka AK: Dengue virus and dendritic cells. Nat Med 6;748-749, 2000 https://doi.org/10.1038/77470
  10. Chaturvedi UC, Tandon P, Mathur A: Effect of immunosuppression on dengue virus infection in mice. J Gen Virol 36;449-458, 1977 https://doi.org/10.1099/0022-1317-36-3-449
  11. Chaturvedi UC, Tandon P, Mathur A, Kumar A: Host defence mechanisms against dengue virus infection of mice. J Gen Virol 39;293-302, 1978 https://doi.org/10.1099/0022-1317-39-2-293
  12. Agrawal DK, Tandon P, Chaturvedi UC, Kumar A: Biochemical study of certain enzymes and metabolites of the carbohydrate metabolism in the skeletal muscle of the dengue virus-infected mice. J Gen Virol 40;399-408, 1978 https://doi.org/10.1099/0022-1317-40-2-399
  13. Chaturvedi UC, Mathur A, Mehrotra RM: Experimentally produced cardiac injury following dengue virus infection. Indian J Pathol Bacteriol 17;218-220, 1974
  14. Mathur A, Arora KL, Chaturvedi UC: Congenital infection of mice with Japanese encephalitis virus. Infect Immun 34;26-29, 1981
  15. Murali-Krishna K, Ravi V, Manjunath R: Japanese encephalitis virus infection of mouse cell lines: ability to prime mice for generation of virus specific cytotoxic T lymphocytes and differences in CTL recognisable viral determinants. Arch Virol 140;127-143, 1995 https://doi.org/10.1007/BF01309728
  16. Lutz MB, Kukutsch NA, Ogilvie ALJ, Robner S, Koch F, Romani, N, Schuler G: An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 223;77-92, 1999 https://doi.org/10.1016/S0022-1759(98)00204-X
  17. Hochrein H, Schlatter B, O'Keeffe M, Wagner C, Schmitz F, Schiemann M, Bauer S, Suter M, Wagner H: Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and independent pathways. Proc Natl Acad Sci USA 101;11416-11421, 2004
  18. Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA: Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med 10;1366-1373, 2004 https://doi.org/10.1038/nm1140
  19. Brooks DG, Trifilo MJ, Edelmann, KH, Teyton L, McGavern DB, Oldstone MB: Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 12;1301-1309, 2006 https://doi.org/10.1038/nm1492
  20. Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM, Crotty S, von Herrath MG: Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med 203;2461-2472, 2006 https://doi.org/10.1084/jem.20061462
  21. Mathur A, Kulshreshtha R, Chaturvedi UC: Evidence for latency of Japanese encephalitis virus in T lymphocytes. J Gen Virol 70;461-465, 1989 https://doi.org/10.1099/0022-1317-70-2-461
  22. Palmer DR, Sun P, Celluzzi C, Bisbing J, Pang S, Sun W, Marovich MA, Burgess T: Differential effects of dengue virus on infected and bystander dendritic cells. J Virol 79;2432-2439, 2005 https://doi.org/10.1128/JVI.79.4.2432-2439.2005
  23. Grutz G: New insights into the molecular mechanism of interleukin-10-mediated immunosuppression. J Leukoc Biol 77;3-15, 2005 https://doi.org/10.1189/jlb.0904484
  24. Ho LJ, Shaio MF, Chang DM, Liao CL, Lai JH: Infection of human dendritic cells by dengue virus activates and primes T cells towards Th0-like phenotype producing both Th1 and Th2 cytokines. Immunol Invest 33;423-437, 2004 https://doi.org/10.1081/IMM-200038680
  25. Avila-Aguero ML, Avila-Aguero CR, Um SL, Soriano-Fallas A, Canas-Coto A, Yan SB: Systemic host inflammatory and coagulation response in the Dengue virus primo-infection. Cytokine 27;173-179, 2004 https://doi.org/10.1016/j.cyto.2004.05.007
  26. Zhou D, Munster A, Winchurch RA: Pathologic concentrations of interleukin 6 inhibit T cell responses via induction of activation of TGF-beta. FASEB J 5;2582-2585, 1991 https://doi.org/10.1096/fasebj.5.11.1868982
  27. Borrow P, Tishon A, Lee S, Xu J, Grewal IS, Oldstone MB, Flavell RA: CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response. J Exp Med 183;2129-2142, 1996 https://doi.org/10.1084/jem.183.5.2129
  28. Sevilla N, McGavern DB, Teng C, Kunz S, Oldstone MB: Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion. J Clin Invest 113;737-745, 2004 https://doi.org/10.1172/JCI20243
  29. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S: Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441;101-105, 2006 https://doi.org/10.1038/nature04734
  30. Chang TH, Liao CL, Lin YL: Flavivirus induces interferon-beta gene expression through a pathway involving RIGI-dependent IRF-3 and PI3K-dependent NF-kappaB activation. Microbes Infect 8;157-171, 2006 https://doi.org/10.1016/j.micinf.2005.06.014
  31. Sato A, Linehan MM, Iwasaki A: Dual recognition of herpes simplex viruses by TLR2 and TLR9 in dendritic cells. Proc Natl Acad Sci USA 103;17343-17348, 2006
  32. Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, Flavell RA: Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA 101;5598-5603, 2004