Coronaviruses cause upper and lower respiratory tract infections ranging from mild infections to severe conditions such as pneumonia and acute respiratory distress syndrome (ARDS). One factor contributing to the pathogenesis of viral infection is the ability to avoid or downregulate the activation of interferon (IFN)-induced antiviral immunity. We show that the seasonal human coronavirus HCoV-229E readily replicated in human lung A549 and human hepatoma Huh7 cells, but the infection did not induce type I or type III IFN gene expression and IFN-induced MxA expression. Total cellular RNA isolated from HCoV-229E-infected A549 or Huh7 cells transfected into uninfected A549 cells failed to induce significant IFN gene expression, indicating that HCoV-229E RNA is likely not recognized by RIG-I-like receptors. However, in similar experiments, influenza A virus (IAV) infection or cellular RNA from IAV-infected cells induced strong IFN responses. Pretreatment of A549 cells with IFN-α showed some inhibitory activity against HCoV-229E replication, but the level of inhibition was weaker than that observed against IAV. Additionally, the ability of type I IFNs to induce MxA protein expression was almost completely blocked in HCoV-229E-infected A549 cells. This phenomenon was observed both at early (8 h) and late (24 h) time points of HCoV-229E infection, indicating that the infection efficiently blocks IFN signaling. Our data show that HCoV-229E can efficiently avoid cellular IFN responses.

IMPORTANCE This study uncovers some of the potential mechanisms by which the seasonal coronavirus HCoV-229E evades host innate immune responses, providing valuable insights into general coronavirus pathogenesis. Unlike IAV, HCoV-229E infection does not induce type I IFN production and IFN-induced antiviral MxA expression. Cellular RNA from HCoV-229E-infected cells fails to induce IFN gene expression, indicating that HCoV-229E virus-specific RNA molecules are not recognized by pattern recognition receptors (PRRs). This immune evasion allows the virus to replicate and produce proteins that further inhibit host defenses. These findings challenge prior reports on IFN responses to seasonal coronaviruses and highlight differences in immune evasion between seasonal and more pathogenic coronaviruses like SARS-CoV-2. By elucidating these mechanisms, the study paves the way for identifying antiviral targets across the coronavirus family and understanding the balance between immune evasion and disease severity, ultimately contributing to the development of broad-spectrum antiviral strategies.