title: Inhibition of the type I interferon response in human dendritic cells by dengue virus infection requires a catalytically active NS2B3 complex.
abstract: Dengue virus (DENV) is the most prevalent arthropod-borne human virus, able to infect and replicate in human dendritic cells (DCs), inducing their activation and the production of proinflammatory cytokines. However, DENV can successfully evade the immune response in order to produce disease in humans. Several mechanisms of immune evasion have been suggested for DENV, most of them involving interference with type I interferon (IFN) signaling. We recently reported that DENV infection of human DCs does not induce type I IFN production by those infected DCs, impairing their ability to prime naive T cells toward Th1 immunity. In this article, we report that DENV also reduces the ability of DCs to produce type I IFN in response to several inducers, such as infection with other viruses or exposure to Toll-like receptor (TLR) ligands, indicating that DENV antagonizes the type I IFN production pathway in human DCs. DENV-infected human DCs showed a reduced type I IFN response to Newcastle disease virus (NDV), Sendai virus (SeV), and Semliki Forest virus (SFV) infection and to the TLR3 agonist poly(I:C). This inhibitory effect is DENV dose dependent, requires DENV replication, and takes place in DENV-infected DCs as early as 2 h after infection. Expressing individual proteins of DENV in the presence of an IFN-alpha/beta production inducer reveals that a catalytically active viral protease complex is required to reduce type I IFN production significantly. These results provide a new mechanism by which DENV evades the immune system in humans.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1124, New York, NY 10029, USA.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Rodriguez-Madoz
authors.forename: Alan
authors.initials: A
authors.lastname: Belicha-Villanueva
authors.forename: Dabeiba
authors.initials: D
authors.lastname: Bernal-Rubio
authors.forename: Joseph
authors.initials: J
authors.lastname: Ashour
authors.forename: Juan
authors.initials: J
authors.lastname: Ayllon
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D003716:Dengue Virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D004285:Dogs; D006801:Humans; D057131:Immune Evasion; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000096:biosynthesis*; D009522:Newcastle disease virus / Q000276:immunology / Q000502:physiology; D012672:Semliki forest virus / Q000276:immunology; D029082:Sendai virus / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication
chemical_list: D017931:DNA Primers; D007370:Interferon Type I; C080102:NS2B protein, flavivirus; D051193:Toll-Like Receptors; D017361:Viral Nonstructural Proteins