Classical swine fever virus npro limits type I interferon induction in plasmacytoid dendritic cells by interacting with interferon regulatory factor 7

Viruses are detected by different classes of pattern recognition receptors that lead to the activation ofinterferon regulatory factors (IRF) and consequently to the induction of alpha/beta interferon (IFN-/). Inturn, efficient viral strategies to escape the type I IFN-induced antiviral mechanisms have evolved. Previousstudies established that pestivirus Npro antagonizes the early innate immune response by targeting thetranscription factor IRF3 for proteasomal degradation. Here, we report that Npro of classical swine fever virus(CSFV) interacts also with IRF7, another mediator of type I IFN induction. We demonstrate that the Znbindingdomain of Npro is essential for the interaction of Npro with IRF7. For IRF3 and IRF7, the DNA-bindingdomain, the central region, and most of the regulatory domain are required for the interaction with Npro.Importantly, the induction of IRF7-dependent type I IFN responses in plasmacytoid dendritic cells (pDC) isreduced after wild-type CSFV infection compared with infection with virus mutants unable to interact withIRF7. This is associated with lower levels of IRF7 in pDC. Consequently, wild-type but not Npro mutantCSFV-infected pDC show reduced responses to other stimuli. Taken together, the results of this study showthat CSFV Npro is capable of manipulating the function of IRF7 in pDC and provides the virus with anadditional strategy to circumvent the innate defense