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      Selective Susceptibility of Human Skin Antigen Presenting Cells to Productive Dengue Virus Infection

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          Abstract

          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.

          Author Summary

          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.

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          Most cited references41

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          Skin immune sentinels in health and disease.

          Human skin and its immune cells provide essential protection of the human body from injury and infection. Recent studies reinforce the importance of keratinocytes as sensors of danger through alert systems such as the inflammasome. In addition, newly identified CD103(+) dendritic cells are strategically positioned for cross-presentation of skin-tropic pathogens and accumulating data highlight a key role of tissue-resident rather than circulating T cells in skin homeostasis and pathology. This Review focuses on recent progress in dissecting the functional role of skin immune cells in skin disease.
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            DC-SIGN (CD209) Mediates Dengue Virus Infection of Human Dendritic Cells

            Dengue virus is a single-stranded, enveloped RNA virus that productively infects human dendritic cells (DCs) primarily at the immature stage of their differentiation. We now find that all four serotypes of dengue use DC-SIGN (CD209), a C-type lectin, to infect dendritic cells. THP-1 cells become susceptible to dengue infection after transfection of DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN), or its homologue L-SIGN, whereas the infection of dendritic cells is blocked by anti–DC-SIGN antibodies and not by antibodies to other molecules on these cells. Viruses produced by dendritic cells are infectious for DC-SIGN– and L-SIGN–bearing THP-1 cells and other permissive cell lines. Therefore, DC-SIGN may be considered as a new target for designing therapies that block dengue infection.
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              CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions.

              The CC chemokine receptor CCR7 has been identified as a key regulator of homeostatic B and T cell trafficking to secondary lymphoid organs. Data presented here demonstrate that CCR7 is also an essential mediator for entry of both dermal and epidermal dendritic cells (DC) into the lymphatic vessels within the dermis while this receptor is dispensable for the mobilization of Langerhans cells from the epidermis to the dermis. Moreover, a distinct population of CD11c(+)MHCII(high) DC showing low expression of the costimulatory molecules CD40, CD80, and CD86 in wild-type animals was virtually absent in skin-draining lymph nodes of CCR7-deficient mice under steady-state conditions. We provide evidence that these cells represent a semimature population of DC that is capable of initiating T cell proliferation under conditions known to induce tolerance. Thus, our data identify CCR7 as a key regulator that governs trafficking of skin DC under both inflammatory and steady-state conditions.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                December 2014
                4 December 2014
                : 10
                : 12
                : e1004548
                Affiliations
                [1 ]Singapore Immunology Network, Agency for Science, Technology and Research, Singapore
                [2 ]School of Biological Sciences, Nanyang Technological University, Singapore
                [3 ]Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
                [4 ]Institute of Molecular Biology, Agency for Science, Technology and Research, Singapore
                [5 ]Division of Rheumatology, University Medicine Cluster, National University Health System, Singapore
                [6 ]Department of Plastic Surgery, Singapore General Hospital, Singapore
                [7 ]Department of General Surgery, Tan Tock Seng Hospital, Singapore
                Purdue University, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: KF FG MH DC. Performed the experiments: DC. Analyzed the data: KF DC BL MP. Contributed reagents/materials/analysis tools: AS PB BKT EYT. Wrote the paper: KF MH DC.

                Article
                PPATHOGENS-D-14-01527
                10.1371/journal.ppat.1004548
                4256468
                25474532
                9498d445-e870-4113-8d1c-4154900e1ea1
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 June 2014
                : 1 November 2014
                Page count
                Pages: 15
                Funding
                This work was supported by the Agency for Science, Technology and Research, (A*STAR), Singapore. DC is a recipient of the Singapore International Graduate Award (SINGA) and was funded by the A*STAR Graduate Academy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                Antigen-Presenting Cells
                Dendritic Cells
                Interdigitating Cells
                Langerhans Cells
                Immunology
                Immune Response
                Lymphocyte Activation
                Classical Immunology
                Medicine and Health Sciences
                Dermatology
                Skin Infections
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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