title: Differences in type I interferon signaling antagonism by dengue viruses in human and non-human primate cell lines.
abstract: OBJECTIVE
  In vitro studies have shown that dengue virus (DENV) can thwart the actions of interferon (IFN)-α/β and prevent the development of an antiviral state in infected cells. Clinical studies looking at gene expression in patients with severe dengue show a reduced expression of interferon stimulated genes compared to patients with dengue fever. Interestingly, there are conflicting reports as to the ability of DENV or other flaviviruses to inhibit IFN-α/β signaling.
  
  
  RESULTS
  In order to determine the relative inhibition of IFN-α/β signaling by DENVs, a method combining flow cytometry and a four-parameter logistic regression model was established. A representative isolate from DENV-1, -3 and -4 and seventeen representative isolates encompassing all DENV-2 genotypes were evaluated. All of the DENVs evaluated in this study were capable of inhibiting IFN-α/β signaling. Most of the strains were able to inhibit IFN-α/β to a degree similar to DENV strain 16681; however, DENV-2 sylvatic strains demonstrated an increased inhibition of phosphorylated signal transducer and activator of transcription (pSTAT1). Surprisingly, we were unable to observe inhibition of pSTAT1 by DENV-2 sylvatic strains or the Asian strain 16681 in non-human primate (NHP) cell lines. Analysis in primary Rhesus macaque dendritic cells suggests that DENVs are capable of inhibiting IFN signaling in these cells. However, contrary to human dendritic cells, production of IFN-α was detected in the supernatant of DENV-infected Rhesus macaque dendritic cells.
  
  
  CONCLUSIONS
  The ability of DENVs to inhibit IFN-α/β signaling is conserved. Although some variation in the inhibition was observed, the moderate differences may be difficult to correlate with clinical outcomes. DENVs were unable to inhibit pSTAT1 in NHP cell lines, but their ability to inhibit pSTAT1 in primary Rhesus macaque dendritic cells suggests that this may be a cell specific phenomena or due to the transformed nature of the cell lines.
authors.affiliation: Centers for Disease Control and Prevention, Division of Vector-Borne Diseases, Dengue Branch, San Juan, Puerto Rico, United States of America.
authors.forename: Freddy A
authors.initials: FA
authors.lastname: Medina
authors.affiliation: University of Puerto Rico Medical Science Campus, Department of Microbiology & Medical Zoology, San Juan, Puerto Rico, United States of America.
authors.forename: Giselle
authors.initials: G
authors.lastname: Torres-Malavé
authors.affiliation: Mercer University School of Medicine, Division of Basic Medical Sciences, Macon, Georgia, United States of America.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Chase
authors.affiliation: Centers for Disease Control and Prevention, Division of Vector-Borne Diseases, Dengue Branch, San Juan, Puerto Rico, United States of America.
authors.forename: Gilberto A
authors.initials: GA
authors.lastname: Santiago
authors.affiliation: Centers for Disease Control and Prevention, Division of Vector-Borne Diseases, Dengue Branch, San Juan, Puerto Rico, United States of America.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Medina
authors.affiliation: Centers for Disease Control and Prevention, Division of Vector-Borne Diseases, Dengue Branch, San Juan, Puerto Rico, United States of America.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Santiago
authors.affiliation: Centers for Disease Control and Prevention, Division of Vector-Borne Diseases, Dengue Branch, San Juan, Puerto Rico, United States of America.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Muñoz-Jordán
mesh_terms: D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000378:metabolism; D003716:Dengue Virus / Q000502:physiology*; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D008253:Macaca mulatta; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014779:Virus Replication
chemical_list: D007370:Interferon Type I; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor