Dengue virus infection differentially regulates endothelial barrier function over time through type I interferon effects.
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.
Liu
Ping
P
Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Woda
Marcia
M
Ennis
Francis A
FA
Libraty
Daniel H
DH
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
D007370:Interferon Type I; D014409:Tumor Necrosis Factor-alpha; D012313:RNA