Temporal activation of NF-κB regulates an interferon-independent innate antiviral response against cytoplasmic RNA viruses

NF-kappaB is known to exert its antiviral innate immune response via the IFN-beta-induced Janus kinase/signal transducers and activators of transcription pathway. However, our current studies have demonstrated that activated NF-kappaB is capable of directly establishing an antiviral state independent of IFN or secreted soluble factor(s) against two highly pathogenic respiratory RNA viruses. Human parainfluenza virus type 3, a mildly cytopathic virus that induced NF-kappaB very early during infection was converted to a virulent virus after NF-kappaB inhibition. In contrast, a highly cytopathic virus, human respiratory syncytial virus that induced NF-kappaB late during infection, was converted to a mildly cytopathic virus after NF-kappaB induction before virus replication. This interconversion of cytopathic phenotypes of viruses after NF-kappaB modulation was further shown to be independent of IFN and soluble secreted factors(s). Moreover, tumor necrosis factor alpha (TNF-alpha) and IL-1beta elicited an antiviral response, which was NF-kappaB-dependent. Thus, NF-kappaB induction directly confers an essential innate antiviral response against human parainfluenza virus type 3 and respiratory syncytial virus, which is independent of IFN-inducible factor(s).