title: Classical swine fever virus N(pro) limits type I interferon induction in plasmacytoid dendritic cells by interacting with interferon regulatory factor 7.
abstract: Viruses are detected by different classes of pattern recognition receptors that lead to the activation of interferon regulatory factors (IRF) and consequently to the induction of alpha/beta interferon (IFN-α/β). In turn, efficient viral strategies to escape the type I IFN-induced antiviral mechanisms have evolved. Previous studies established that pestivirus N(pro) antagonizes the early innate immune response by targeting the transcription factor IRF3 for proteasomal degradation. Here, we report that N(pro) of classical swine fever virus (CSFV) interacts also with IRF7, another mediator of type I IFN induction. We demonstrate that the Zn-binding domain of N(pro) is essential for the interaction of N(pro) with IRF7. For IRF3 and IRF7, the DNA-binding domain, the central region, and most of the regulatory domain are required for the interaction with N(pro). Importantly, the induction of IRF7-dependent type I IFN responses in plasmacytoid dendritic cells (pDC) is reduced after wild-type CSFV infection compared with infection with virus mutants unable to interact with IRF7. This is associated with lower levels of IRF7 in pDC. Consequently, wild-type but not N(pro) mutant CSFV-infected pDC show reduced responses to other stimuli. Taken together, the results of this study show that CSFV N(pro) is capable of manipulating the function of IRF7 in pDC and provides the virus with an additional strategy to circumvent the innate defense.
authors.affiliation: Institute of Virology and Immunoprophylaxis (IVI), Mittelhäusern, Switzerland.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Fiebach
authors.forename: Laurence
authors.initials: L
authors.lastname: Guzylack-Piriou
authors.forename: Sylvie
authors.initials: S
authors.lastname: Python
authors.forename: Artur
authors.initials: A
authors.lastname: Summerfield
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ruggli
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D006692:Classical Swine Fever Virus / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D047468:Immunoprecipitation; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism*; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D051192:Receptors, Pattern Recognition / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
chemical_list: D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D051192:Receptors, Pattern Recognition; D014764:Viral Proteins; D010450:Endopeptidases; C505229:N(pro) protein, swine fever virus; D015032:Zinc