Pseudorabies Virus IE180 Inhibits Virus Replication by Activating the Type I Interferon Pathway

The immediate-early protein IE180 of <i>pseudorabies virus</i> (PRV) is a multifunctional regulator of viral and host gene expression. However, its role in modulating antiviral immune responses remains poorly understood. Here, we demonstrate that IE180 overexpression significantly inhibits PRV and <i>H1N1 influenza virus</i> replication in Hep2 and A549 cells, respectively. Mechanistically, IE180 activates the type I interferon (IFN-I) pathway by enhancing IFN-β promoter activity and IFN transcription, leading to upregulated expression of interferon-stimulated genes (<i>ISGs</i>). Notably, IE180 failed to suppress PRV or H1N1 replication in Vero cells, which lack functional IFN-I signaling, confirming the dependence of its antiviral function on the IFN-I pathway. Domain mapping revealed that the ICP4-Like2 domain of IE180 is critical for IFN-β activation and antiviral activity. These findings establish IE180 as a novel viral immunomodulator that activates host innate immunity to restrict viral replication, providing insights into PRV-host interactions and potential therapeutic strategies.