Dengue is a growing global concern with 390 million people infected each year. Dengue virus (DENV) is transmitted by mosquitoes, thus host cells in the skin are the first point of contact with the virus. Human skin contains several populations of antigen-presenting cells which could drive the immune response to DENV in vivo: epidermal Langerhans cells (LCs), three populations of dermal dendritic cells (DCs), and macrophages. Using samples of normal human skin we detected productive infection of CD14 + and CD1c + DCs, LCs and dermal macrophages, which was independent of DC-SIGN expression. LCs produced the highest viral titers and were less sensitive to IFN-β. Nanostring gene expression data showed significant up-regulation of IFN-β, STAT-1 and CCL5 upon viral exposure in susceptible DC populations. In mice infected intra-dermally with DENV we detected parallel populations of infected DCs originating from the dermis and migrating to the skin-draining lymph nodes. Therefore dermal DCs may simultaneously facilitate systemic spread of DENV and initiate the adaptive anti-viral immune response.
Dengue virus (DENV) is transmitted by mosquitoes with skin as point of entry for the virus. Here, we investigated DENV infection in primary human skin cells and their initial immune response. Using skin from normal human donors for infection with DENV in vitro we identified antigen-presenting cells (APCs) as main targets of DENV. Further analysis showed that only distinct subsets of dendritic cells (DCs) and macrophages were infected and efficiently produced viral progeny. Langerhans cells were most susceptible to infection despite lacking DC-SIGN, a previously described DENV receptor. Infection of the other DC subsets and macrophages was also independent of DC-SIGN expression. Genes of the interferon pathway and CCL5, a chemokine attracting immune cells to sites of inflammation, were highly up-regulated in the infected DC subsets. Using a mouse infection model, we showed that murine dermal DCs were also susceptible to DENV and migrated to draining lymph nodes. At the same time infiltrating monocytes differentiated into monocyte-derived cells at the site of infection and became an additional target for DENV in vivo. These data demonstrate that DENV differentially infects and activates primary human skin APCs and that infected cell types individually contribute to inflammation and the adaptive response.