title: Dramatic caspase-dependent apoptosis in antibody-enhanced dengue virus infection of human mast cells.
abstract: Severe forms of dengue virus disease, known as dengue hemorrhagic fever and dengue shock syndrome, result from an aberrant immune response involving antibody-dependent enhancement of infection, thrombocytopenia, and a loss of vascular integrity, culminating in hemorrhage, shock, and in some cases, death. Several studies have indicated that dengue virus infection results in the induction of apoptosis of certain cells believed to be contributory players in dengue pathogenesis. However, none have specifically examined the role of antibody enhancement in the context of induction of apoptosis. Here, we show that antibody-enhanced dengue virus infection of the FcR-bearing mast cell/basophil KU812 cell line results in a massive induction of apoptosis. Confocal microscopy and flow cytometry indicate two distinct subpopulations consisting of productively infected cells and apoptotic-uninfected bystanders. Apoptosis was found to be caspase-dependent, involving global caspase activation and cleavage of poly-ADP-ribose polymerase (PARP) and D4-guanosine diphosphate dissociation inhibitor (D4-GDI). Additional FcR-bearing cells, including K562, U937, and human mast cell 1 (HMC-1), were analyzed for apoptosis induction following infection. Although all cells displayed high susceptibility to antibody-enhanced dengue virus infection, only cells of a mast cell phenotype (KU812 and HMC-1) were found to undergo apoptosis. Dengue-induced apoptosis of KU812 cells was shown to require antibody-enhanced dengue virus infection by blockade of FcgammaRII. Transfection of KU812 cells with L-SIGN/DC-SIGNR was able to overcome the requirement for antibody enhancement with regard to dengue virus infection and apoptosis.
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Brown
authors.forename: Yan Y
authors.initials: YY
authors.lastname: Huang
authors.forename: Jean S
authors.initials: JS
authors.lastname: Marshall
authors.forename: Christine A
authors.initials: CA
authors.lastname: King
authors.forename: David W
authors.initials: DW
authors.lastname: Hoskin
authors.forename: Robert
authors.initials: R
authors.lastname: Anderson
mesh_terms: D019067:Antibody-Dependent Enhancement; D017209:Apoptosis / Q000502:physiology*; D001491:Basophils / Q000276:immunology / Q000473:pathology; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002460:Cell Line; D024161:Collagen Type XI / Q000378:metabolism; D003715:Dengue / Q000276:immunology / Q000473:pathology; D003716:Dengue Virus / Q000276:immunology* / Q000502:physiology; D004789:Enzyme Activation; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000276:immunology; D037181:Lectins, C-Type / Q000096:biosynthesis; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D017452:Receptors, IgG / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
chemical_list: C569658:ARHGDIB protein, human; C433029:CLEC4M protein, human; C499319:COL11A2 protein, human; D061945:Caspase Inhibitors; D015815:Cell Adhesion Molecules; D024161:Collagen Type XI; D020730:Guanine Nucleotide Dissociation Inhibitors; D007135:Immunoglobulin Variable Region; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D025521:Tumor Suppressor Proteins; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D020169:Caspases