title: Dermal CD14(+) Dendritic Cell and Macrophage Infection by Dengue Virus Is Stimulated by Interleukin-4.
abstract: Dengue virus (DENV) is responsible for the most prevalent arthropod-borne viral infection in humans. Events decisive for disease development occur in the skin after virus inoculation by the mosquito. Yet, the role of human dermis-resident immune cells in dengue infection and disease remains elusive. Here we investigated how dermal dendritic cells (dDCs) and macrophages (dMs) react to DENV and impact on immunopathology. We show that both CD1c(+) and CD14(+) dDC subsets were infected, but viral load greatly increased in CD14(+) dDCs upon IL-4 stimulation, which correlated with upregulation of virus-binding lectins Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin (DC-SIGN/CD209) and mannose receptor (CD206). IL-4 also enhanced T-cell activation by dDCs, which was further increased upon dengue infection. dMs purified from digested dermis were initially poorly infected but actively replicated the virus and produced TNF-α upon lectin upregulation in response to IL-4. DC-SIGN(+) cells are abundant in inflammatory skin with scabies infection or Th2-type dermatitis, suggesting that skin reactions to mosquito bites heighten the risk of infection and subsequent immunopathology. Our data identify dDCs and dMs as primary arbovirus target cells in humans and suggest that dDCs initiate a potent virus-directed T-cell response, whereas dMs fuel the inflammatory cascade characteristic of dengue fever.
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, IBMC, University of Strasbourg, Strasbourg, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Schaeffer
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, IBMC, University of Strasbourg, Strasbourg, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Flacher
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, IBMC, University of Strasbourg, Strasbourg, France.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Papageorgiou
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, IBMC, University of Strasbourg, Strasbourg, France; Current address: Chemistry and Biology of Membranes and Nanoobjects, CBMN, UMR 5248, CNRS-University of Bordeaux1-IPB, 33600 Pessac, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Decossas
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, IBMC, University of Strasbourg, Strasbourg, France.
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Fauny
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, IBMC, University of Strasbourg, Strasbourg, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Krämer
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, IBMC, University of Strasbourg, Strasbourg, France. Electronic address: c.mueller@ibmc-cnrs.unistra.fr.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mueller
mesh_terms: D034861:Abdominal Wall; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003715:Dengue / Q000821:virology; D003716:Dengue Virus / Q000276:immunology / Q000472:pathogenicity*; D004797:Enzyme-Linked Immunosorbent Assay; D000078404:Epidermal Cells; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D007801:Langerhans Cells / Q000166:cytology / Q000276:immunology; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D018613:Microscopy, Confocal; D011956:Receptors, Cell Surface / Q000378:metabolism; D012680:Sensitivity and Specificity; D017193:Skin Diseases, Viral / Q000378:metabolism* / Q000503:physiopathology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D015847:Interleukin-4; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin