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 vaccine. 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 leukocyte 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.

Role of CD8+T Cells and Lymphoid Dendritic Cells in Protection from Ocular Herpes Simplex Virus 1 Challenge in Immunized Mice

“…The concept that CD8␣ ϩ DCs may act to exacerbate HSV-1 latency rather than play a protective role in mice is consistent with the reports of the deleterious effects of certain populations of DCs in the control of vaccinia virus (76), HIV-1 (77,78), and dengue virus (79).…”

Mosquito Saliva Serine Protease Enhances Dissemination of Dengue Virus into the Mammalian Host

“…We hypothesize that mosquito saliva serine proteases liquefy dermal tissue by proteolyzing ECM components. Proteolysis increases cellular mobility and inflammatory signals within the dermis and enhances interaction between immobilized virions and permissive cell types, such as Langerhans cells or macrophage (29). Irritant and allergen-dependent modulation of the dermal environment has previously been shown to induce migration of Langerhans cells to draining lymph nodes (29)(30)(31)(32).…”

“…Proteolysis increases cellular mobility and inflammatory signals within the dermis and enhances interaction between immobilized virions and permissive cell types, such as Langerhans cells or macrophage (29). Irritant and allergen-dependent modulation of the dermal environment has previously been shown to induce migration of Langerhans cells to draining lymph nodes (29)(30)(31)(32). This is correlated with a fibroblast-and IL-10-dependent switch of Langerhans cells to a macrophage-like phenotype and may require the breakdown of integrin-mediated interactions with extracellular matrix components (32,33).…”

Transient Monocytosis Subjugates Low Platelet Count in Adult Dengue Patients

“…Although DENV infection of monocytes/macrophages is very inefficient [10,16,38], the severity of DENV infection has been linked to the number of DENV antigen-positive monocytes and their increased activation [39]. A sequential cascade of events including low platelet counts and prolonged aPTT coupled with transient monocytosis, enhancing phagocytic activity during the course of DENV infection, may result in releasing a large amount of soluble factors to induce DHF [3].…”