title: Dengue virus type 2 antagonizes IFN-alpha but not IFN-gamma antiviral effect via down-regulating Tyk2-STAT signaling in the human dendritic cell.
abstract: The immunopathogenesis mechanism of dengue virus (DV) infection remains elusive. We previously showed that the target of DV in humans is dendritic cells (DCs), the primary sentinels of immune system. We also observed that despite the significant amount of IFN-alpha induced; DV particles remain massively produced from infected DCs. It suggests that DV may antagonize the antiviral effect of IFN-alpha. Recent work in animal studies demonstrated the differential critical roles of antiviral cytokines, namely IFN-alpha/IFN-beta and IFN-gamma, in blocking early viral production and in preventing viral-mediated disease, respectively. In this study, we examined the effects of IFN-alpha and IFN-gamma in DV infection of monocyte-derived DCs. We showed that the preinfection treatment with either IFN-alpha or IFN-gamma effectively armed DCs and limited viral production in infected cells. However, after infection, DV developed mechanisms to counteract the protection from lately added IFN-alpha, but not IFN-gamma. Such a selective antagonism on antiviral effect of IFN-alpha, but not IFN-gamma, correlated with down-regulated tyrosine-phosphorylation and DNA-binding activities of STAT1 and STAT3 transcription factors by DV. Furthermore, subsequent studies into the underlying mechanisms revealed that DV attenuated IFN-alpha-induced tyrosine-phosphorylation of Tyk2, an upstream molecule of STAT activation, but had no effect on expression of both IFN-alpha receptor 1 and IFN-alpha receptor 2. Moreover, DV infection by itself could activate STAT1 and STAT3 through IFN-alpha-dependent and both IFN-alpha-dependent and IFN-alpha-independent mechanisms, respectively. These observations provide very useful messages with physiological significance in investigation of the pathogenesis, the defense mechanisms of human hosts and the therapeutic considerations in DV infection.
authors.affiliation: Division of Gerontology Research, National Health Research Institute, Academia Sinica, Taipei, Taiwan.
authors.forename: Ling-Jun
authors.initials: LJ
authors.lastname: Ho
authors.forename: Li-Feng
authors.initials: LF
authors.lastname: Hung
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Weng
authors.forename: Wan-Lin
authors.initials: WL
authors.lastname: Wu
authors.forename: Ping
authors.initials: P
authors.lastname: Chou
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Deh-Ming
authors.initials: DM
authors.lastname: Chang
authors.forename: Tong-Yuan
authors.initials: TY
authors.lastname: Tai
authors.forename: Jenn-Haung
authors.initials: JH
authors.lastname: Lai
mesh_terms: D000998:Antiviral Agents / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D003716:Dengue Virus / Q000145:classification / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D053634:TYK2 Kinase; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D014443:Tyrosine / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D053633:Receptor, Interferon alpha-beta; D014443:Tyrosine; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human