Negative Regulation of Interferon-β Gene Expression during Acute and Persistent Virus Infections

Abstract

The production of type I interferons (IFNs) in response to viral infections is critical for antiviral immunity. However, IFN production is transient, and continued expression can lead to inflammatory or autoimmune diseases. Thus, understanding the mechanisms underlying the negative regulation of IFN expression could lead to the development of novel therapeutic approaches to the treatment of these diseases. We report that the transcription factor IRF3 plays a central role in the negative regulation of interferon-β (IFNβ) expression during both acute and persistent (chronic) virus infections. We show that the degradation of IRF3 during acute infections, rather than the activation of transcriptional repressors, leads to the down regulation of IFNβ expression. We also show that the block to IFNβ expression in mouse embryonic fibroblasts that are persistently infected with Sendai virus (SeV) correlates with the absence of transcriptionally active IRF3. Remarkably, ongoing protein synthesis and viral replication are required to maintain repression of the IFNβ gene in persistently infected cells, as the gene can be activated by the protein synthesis inhibitor cycloheximide, or by the antiviral drug ribavirin. Finally, we show that the SeV V protein inhibits IRF3 activity in persistently infected cells. Thus, in conjunction with the known interference with STAT1 by the SeV C protein, both IFN activation and its signaling pathways are blocked in persistently infected cells. We conclude that the transcription factor IRF3 is targeted for turnover and inactivation through distinct mechanisms from both the host cells and virus, leading to the inhibition of IFNβ gene expression during acute and persistent viral infections. These observations show that IRF3 plays a critical role, not only in the activation of the IFNβ gene, but also in the controlling the duration of its expression. (284 words)

Measles Virus C Protein Interferes with Beta Interferon Transcription in the Nucleus

“…1C). Whether this can be entirely attributed to the recently observed inhibition of NF-B activity (59), which plays a role in early IFN-␤ induction in human cells (21), or whether V has additional targets downstream of MDA5 and TBK-1, as was reported for V proteins of rubulaviruses and of SeV (32,69), remains to be clarified. In any case, it is obvious that both V and C proteins of MV do contribute to inhibition of MDA5-independent IFN-␤ induction.…”

Viral degradasome hijacks mitochondria to suppress innate immunity

“…Attempts are currently being made to immunoprecipitate the NSD complex using the FLAG tag attached to NS1/ NS2 to determine its protein composition and to find out whether ubiquitin pathway enzymes and/or proteasomal subunits are integral components of NSD or are adventitiously associated. Moreover, finding of non-proteasomal proteases in the NSD will help explain the incomplete inhibition of NSD degradative activity by MG132; in fact, complex roles of both proteasomal and non-proteasomal proteases have been recently inferred in the negative regulation of IRF3 during viral infection [57].…”

Role of Interferon Regulatory Factor 3-Mediated Apoptosis in the Establishment and Maintenance of Persistent Infection by Sendai Virus

“…Hence, in principle, some cell types may be more prone to PI than others. Ye and Maniatis tested several cell lines for survival after SeV infection (27). Most of the cell lines died, but one MEF line survived and became PI.…”