title: Role of dendritic cells in antibody-dependent enhancement of dengue virus infection.
abstract: Dengue viruses (DV), composed of four distinct serotypes (DV1 to DV4), cause 50 to 100 million infections annually. Durable homotypic immunity follows infection but may predispose to severe subsequent heterotypic infections, a risk conferred in part by the immune response itself. Antibody-dependent enhancement (ADE), a process best described in vitro, is epidemiologically linked to complicated DV infections, especially in Southeast Asia. Here we report for the first time the ADE phenomenon in primary human dendritic cells (DC), early targets of DV infection, and human cell lines bearing Fc receptors. We show that ADE is inversely correlated with surface expression of DC-SIGN (DC-specific intercellular adhesion molecule-3-grabbing nonintegrin) and requires Fc gamma receptor IIa (FcgammaRIIa). Mature DC exhibited ADE, whereas immature DC, expressing higher levels of DC-SIGN and similar FcgammaRIIa levels, did not undergo ADE. ADE results in increased intracellular de novo DV protein synthesis, increased viral RNA production and release, and increased infectivity of the supernatants in mature DC. Interestingly, tumor necrosis factor alpha and interleukin-6 (IL-6), but not IL-10 and gamma interferon, were released in the presence of dengue patient sera but generally only at enhancement titers, suggesting a signaling component of ADE. FcgammaRIIa inhibition with monoclonal antibodies abrogated ADE and associated downstream consequences. DV versatility in entry routes (FcgammaRIIa or DC-SIGN) in mature DC broadens target options and suggests additional ways for DC to contribute to the pathogenesis of severe DV infection. Studying the cellular targets of DV infection and their susceptibility to ADE will aid our understanding of complex disease and contribute to the field of vaccine development.
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Division of Retrovirology, Department of Vaccine R&D, Walter Reed Army Institute of Research, 13 Taft Ct., Suite 200, Rockville, MD 20850, USA.
authors.forename: Kobporn
authors.initials: K
authors.lastname: Boonnak
authors.forename: Bonnie M
authors.initials: BM
authors.lastname: Slike
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Burgess
authors.forename: Randall M
authors.initials: RM
authors.lastname: Mason
authors.forename: Shuenn-Jue
authors.initials: SJ
authors.lastname: Wu
authors.forename: Peifang
authors.initials: P
authors.lastname: Sun
authors.forename: Kevin
authors.initials: K
authors.lastname: Porter
authors.forename: Irani Fianza
authors.initials: IF
authors.lastname: Rudiman
authors.forename: Djoko
authors.initials: D
authors.lastname: Yuwono
authors.forename: Pilaipan
authors.initials: P
authors.lastname: Puthavathana
authors.forename: Mary A
authors.initials: MA
authors.lastname: Marovich
mesh_terms: D019067:Antibody-Dependent Enhancement; D015703:Antigens, CD / Q000276:immunology; D000954:Antigens, Surface / Q000032:analysis; D001210:Asia, Southeastern; D015815:Cell Adhesion Molecules / Q000032:analysis; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D003715:Dengue / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D037181:Lectins, C-Type / Q000032:analysis; D012367:RNA, Viral / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000032:analysis; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D015815:Cell Adhesion Molecules; D007371:Interferon-gamma; D016753:Interleukin-10; D015850:Interleukin-6; D037181:Lectins, C-Type; D012367:RNA, Viral; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C080568:Fc gamma receptor IIA