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Human skin Langerhans cells are targets of dengue virus infection


Dengue virus (DV), an arthropod-borne flavivirus, causes a febrile illness for which there is no antiviral treatment and no vaccine1,2. Macrophages are important in dengue pathogenesis; however, the initial target cell for DV infection remains unknown. As DV is introduced into human skin by mosquitoes of the genus Aedes, we undertook experiments to determine whether human dendritic cells (DCs) were permissive for the growth of DV. Initial experiments demonstrated that blood-derived DCs were 10-fold more permissive for DV infection than were monocytes or macrophages. We confirmed this with human skin DCs (Langerhans cells and dermal/interstitial DCs). Using cadaveric human skin explants, we exposed skin DCs to DV ex vivo. Of the human leukoctye antigen DR-positive DCs that migrated from the skin, emigrants from both dermis and epidermis, 60–80% expressed DV antigens. These observations were supported by histologic findings from the skin rash of a human subject who received an attenuated tetravalent dengue vaccine. Immunohistochemistry of the skin showed CD1a-positive DCs double-labeled with an antibody against DV envelope glycoprotein. These data demonstrate that human skin DCs are permissive for DV infection, and provide a potential mechanism for the transmission of DV into human skin.

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Figure 1: Infection of blood-derived DCs with DV.
Figure 2: Cytofluorometry of DV-infected DCs.
Figure 3: Infection of skin DCs with DV.


  1. Halstead, S.B. Pathogenesis of dengue: challenges to molecular biology. Science 239, 476–481 ( 1988).

    CAS  Article  Google Scholar 

  2. Rigau-Perez, J. et al. Dengue and dengue heamorrhagic fever. Lancet 352, 971–977 (1998).

    CAS  Article  Google Scholar 

  3. Taweechaisupapong, S. et al. Langerhans cell density and serological changes following intradermal immunisation of mice with dengue 2 virus. J. Med. Microbiol. 45, 138–145 ( 1996).

    CAS  Article  Google Scholar 

  4. Taweechaisupapong, S., Sriurairatana, S., Angsubhakorn, S., Yoksan, S. & Bhamarapravati, N. In vivo and in vitro studies of the morphological change in the monkey epidermal Langerhans cells following exposure to dengue 2 virus. Southeast Asian J. Trop. Med. Public Health 27, 664–672 (1996).

    CAS  PubMed  Google Scholar 

  5. Cella, M. et al. Maturation, activation, and protection of dendritic cells induced by double-stranded RNA. J. Exp. Med. 189, 821–829 (1999).

    CAS  Article  Google Scholar 

  6. Rice, C.M. in Fields Virology (eds. Fields, B.N., Knipe, D.M. & Howley, P.M.) 931–959 (Lippincott-Raven, Philadelphia, 1996).

    Google Scholar 

  7. Pope, M., Betjes, M.G.H., Hirmand, H., Hoffman, L. & Steinman, R. Both dendritic cells and memory T lymphocytes emigrate from organ cultures of human skin and form distinctive dendritic-T-cell conjugates. J. Invest. Dermatol. 104 , 11–17 (1995).

    CAS  Article  Google Scholar 

  8. Labuda, M. et al. Importance of localized skin infection in tick-borne encephalitis virus transmission. Virology 219, 357– 366 (1996).

    CAS  Article  Google Scholar 

  9. O'Sullivan, M.K.H. The differentiation state of monocytic cells affects their susceptibility to infection and the effects of infection by dengue virus. J. Gen. Virol. 75, 2387–2392 ( 1994).

    Article  Google Scholar 

  10. Morens, D. M., Halstead, S.B. & Marchette, N.J. Profiles of antibody-dependent enhancement of dengue virus type 2 infection. Microb. Pathog. 3, 231–237 (1987).

    CAS  Article  Google Scholar 

  11. Morens, D.M., Larsen, L.K. & Halstead, S.B. Study of the distribution of antibody-dependent enhancement determinants on dengue 2 isolates using dengue 2-derived monoclonal antibodies . J. Med. Virol. 22, 163– 167 (1987).

    CAS  Article  Google Scholar 

  12. Chen, Y. et al. Dengue virus infectivity depends on envelope protein binding to target cell heparin sulfate. Nature Med. 3, 866–871 (1997).

    CAS  Article  Google Scholar 

  13. Halstead, S., O'Rourke, E. & Allison, A. Dengue viruses and mononuclear phagocytes. J. Exp. Med. 146, 218–229 (1977).

    CAS  Article  Google Scholar 

  14. Frankel, S.S. et al. Neutralizing monoclonal antibodies block human immunodeficiency virus type 1 infection of dendritic cells and transmission to T cells. J. Virol. 72, 9788–9794 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Pope, M. et al. Human immunodeficiency virus type 1 strains of subtypes B and E replicate in cutaneous dendritic cell T-cell mixtures without displaying subtype-specific tropism. J. Virol. 71, 8001–8007 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Henchal, E.A., McCown, J.M., Burke, D.S., Seguin, M.C. & Brandt, W.E. Epitopic analysis of antigenic determinants on the surface of dengue-2 virions using monoclonal antibodies . Am. J. Trop. Med. Hyg. 34, 162– 169 (1985).

    CAS  Article  Google Scholar 

  17. Raviprakash, K., Sinha, M., Hayes, C.G. & Porter, K.R. Conversion of dengue virus replication form RNA (RF) to replicative intermediate (RI) by nonstructural proteins NS-5 and NS-3. Am. J. Trop. Med. Hyg. 58, 90–95 (1998).

    CAS  Article  Google Scholar 

  18. Morens, DM. Simplified plaque reduction neutralization assay for dengue viruses by semimicro methods in BHK-21 cells: Comparison of the BHK suspension test with standard plaque reduction neutralization. J. Clin. Microbiol. 22, 250–253 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu, S.-J.L. et al. Evaluation of the severe combined immunodeficient (SCID) mouse as an animal model for dengue viral infection. Am. J. Trop. Med. Hyg. 52, 468–476 ( 1995).

    CAS  Article  Google Scholar 

  20. Frankel, S.S. et al. Active replication of HIV-1 at the lymphoepithelial surface of the tonsil. Am. J. Pathol. 151, 89– 96 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. de Saint-Vis, B. et al. A novel lysosome-associated membrane glycoprotein, DC-LAMP, induced upon DC maturation, is transiently expressed in MHC class II compartment . Immunity 9, 325–336 (1998).

    CAS  Article  Google Scholar 

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The authors thank N. Bhamarapravati, R. Steinman, S. Halstead and J. McNeil for scientific guidance and manuscript review; and D. Ford for assistance with graphics. This work was supported in part by cooperative agreement number DAMD17-93-V 3004, between the US Army Medical Research and Materiel Command and the Henry M. Jackson Foundation for the Advancement of Military Medicine and by the Military Infectious Disease Research Program ONR account 821.103. PATH.1918. The views and opinions expressed herein are those of the authors and do not purport to reflect the official policy or position of the Department of Defense. The human clinical trial was conducted in accordance with a human subjects protocol approved by The Walter Reed Army Medical Center Committee for the Protection of Human Subjects.

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Correspondence to Sarah Schlesinger Frankel.

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Wu, SJ., Grouard-Vogel, G., Sun, W. et al. Human skin Langerhans cells are targets of dengue virus infection. Nat Med 6, 816–820 (2000).

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