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Human skin Langerhans cells are targets of dengue virus infection

Abstract

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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Acknowledgements

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