Viruses commonly antagonize innate immune pathways that are primarily driven by
nuclear factor kappa B (NF-κB),
interferon regulatory factor (IRF), and the signal transducer and activator of transcription
proteins (STAT) family of
transcription factors. Such a strategy allows viruses to evade immune surveillance and maximize their replication. Using an unbiased transcriptome sequencing (
RNA-seq)-based approach to measure gene expression induced by transfected viral genomic
RNA (vgRNA) and
reovirus infection, we discovered that mammalian reovirus inhibits host cell innate immune signaling. We found that, while vgRNA and
reovirus infection both induce a similar IRF-dependent gene expression program, gene expression driven by the NF-κB family of
transcription factors is lower in infected cells. Potent agonists of NF-κB such as
tumor necrosis factor alpha (TNF-α) and vgRNA failed to induce NF-κB-dependent gene expression in infected cells. We demonstrate that NF-κB signaling is blocked due to loss of critical members of the inhibitor of kappa B
kinase (IKK) complex, NF-κB essential modifier (NEMO), and IKKβ. The loss of the IKK complex components prevents nuclear translocation and phosphorylation of NF-κB, thereby preventing gene expression. Our study demonstrates that
reovirus infection selectively blocks NF-κB, likely to counteract its
antiviral effects and promote efficient viral replication.IMPORTANCE Host cells mount a response to curb virus replication in infected cells and prevent spread of virus to neighboring, as yet uninfected, cells. The NF-κB family of
proteins is important for the cell to mediate this response. In this study, we show that in cells infected with mammalian reovirus, NF-κB is inactive. Further, we demonstrate that NF-κB is rendered inactive because
virus infection results in reduced levels of upstream intermediaries (called IKKs) that are needed for NF-κB function. Based on previous evidence that active NF-κB limits
reovirus infection, we conclude that inactivating NF-κB is a viral strategy to produce a cellular environment that is favorable for virus replication.