title: Dengue virus infection differentially regulates endothelial barrier function over time through type I interferon effects.
abstract: BACKGROUND
  The morbidity and mortality resulting from dengue hemorrhagic fever (DHF) are largely caused by endothelial barrier dysfunction and a unique vascular leakage syndrome. The mechanisms that lead to the location and timing of vascular leakage in DHF are poorly understood. We hypothesized that direct viral effects on endothelial responsiveness to inflammatory and angiogenesis mediators can explain the DHF vascular leakage syndrome.
  
  
  METHODS
  We used an in vitro model of human endothelium to study the combined effects of dengue virus (DENV) type 2 (DENV2) infection and inflammatory mediators on paracellular macromolecule permeability over time.
  
  
  RESULTS
  Over the initial 72 h after infection, DENV2 suppressed tumor necrosis factor (TNF)-alpha-mediated hyperpermeability in human umbilical vein endothelial cell (HUVEC) monolayers. This suppressive effect was mediated by type I interferon (IFN). By 1 week, TNF-alpha stimulation of DENV2-infected HUVECs synergistically increased cell cycling, angiogenic changes, and macromolecule permeability. This late effect could be prevented by the addition of exogenous type I IFN.
  
  
  CONCLUSIONS
  DENV infection of primary human endothelial cells differentially modulates TNF-alpha-driven angiogenesis and hyperpermeability over time. Type I IFN plays a central role in this process. Our findings suggest a rational model for the DHF vascular leakage syndrome.
authors.affiliation: Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Marcia
authors.initials: M
authors.lastname: Woda
authors.forename: Francis A
authors.initials: FA
authors.lastname: Ennis
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Libraty
mesh_terms: D000818:Animals; D002460:Cell Line; D009033:Culicidae; D003716:Dengue Virus / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000821:virology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage / Q000494:pharmacology*; D046228:Microarray Analysis; D012313:RNA / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007370:Interferon Type I; D014409:Tumor Necrosis Factor-alpha; D012313:RNA