title: Autophagy facilitates antibody-enhanced dengue virus infection in human pre-basophil/mast cells.
abstract: BACKGROUND
  Dengue virus (DENV) infection can cause severe hemorrhagic disease in humans. Although the pathogenic mechanisms underlying severe DENV disease remain unclear, one of the possible contributing factors is antibody-dependent enhancement (ADE) which occurs when sub-neutralizing antibodies derived from a previous DENV infection enhance viral infection through interaction between virus-antibody complexes and FcR-bearing cells, such as macrophages and basophil/mast cells. Although recent reports showed that DENV induces autophagy, the relationship between antibody-enhanced DENV infection and autophagy is not clear.
  
  
  RESULTS
  We showed that sub-neutralizing antibodies derived from dengue patient sera enhanced DENV infection and autophagy in the KU812 pre-basophil-like cell line as well as the HMC-1 immature mast cell line. Antibody-enhanced DENV infection of KU812 cells increased the number of autophagosome vesicles, LC3 punctation, LC3-II accumulation, and p62 degradation over that seen in cells infected with DENV alone. The percentages of DENV envelope (E) protein-positive cells and LC3 puncta following antibody-enhanced DENV infection of KU812 cells were reduced by the autophagy inhibitor 3-MA. Antibody-enhanced DENV infection of HMC-1 cells showed co-localization of DENV E protein and dsRNA with autophagosomes, which was inhibited by 3-MA treatment. Furthermore, DENV infection and replication were reduced when KU812 cells were transfected with the autophagy-inhibiting Atg4BC74A mutant.
  
  
  CONCLUSIONS
  Our results demonstrate a significant induction of autophagy in antibody-enhanced DENV infection of pre-basophil-like KU812 and immature mast cell-like HMC-1 cells. Also, autophagy plays an important role in DENV infection and replication in these cells. Given the importance of ADE and FcR-bearing cells such as monocytes, macrophages and basophil/mast cells in dengue disease, the results provide insights into dengue pathogenesis and therapeutic means of control.
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Fang
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Wan
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: Yi-Tien
authors.initials: YT
authors.lastname: Lu
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Ju-Han
authors.initials: JH
authors.lastname: Yao
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: Li-Jin
authors.initials: LJ
authors.lastname: Hsu
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Canada.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Brown
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Canada.
authors.forename: Jean S
authors.initials: JS
authors.lastname: Marshall
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Anderson
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
mesh_terms: D000914:Antibodies, Viral / Q000276:immunology*; D019067:Antibody-Dependent Enhancement / Q000276:immunology*; D001343:Autophagy / Q000276:immunology*; D001491:Basophils / Q000276:immunology; D002460:Cell Line; D003715:Dengue / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D008407:Mast Cells / Q000276:immunology / Q000821:virology; D014759:Viral Envelope Proteins / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D014759:Viral Envelope Proteins