The immune system defends against invading pathogens through the rapid activation of innate immune signaling pathways. Interferon regulatory factor 3 (IRF3) is a key transcription factor activated in response to virus infection and is largely responsible for establishing an antiviral state in the infected host. Studies in Irf3−/−mice have demonstrated the absence of IRF3 imparts a high degree of susceptibility to a wide range of viral infections. Virus infection causes the activation of IRF3 to transcribe type-I interferon (e.g., IFNβ), which is responsible for inducing the interferon-stimulated genes (ISGs), which act at specific stages to limit virus replication. In addition to its transcriptional function, IRF3 is also activated to trigger apoptosis of virus-infected cells, as a mechanism to restrict virus spread within the host, in a pathway called RIG-I-like receptor-induced IRF3 mediated pathway of apoptosis (RIPA). These dual functions of IRF3 work in concert to mediate protective immunity against virus infection. These two pathways are activated differentially by the posttranslational modifications (PTMs) of IRF3. Moreover, PTMs regulate not only IRF3 activation and function, but also protein stability. Consequently, many viruses utilize viral proteins or hijack cellular enzymes to inhibit IRF3 functions. This review will describe the PTMs that regulate IRF3′s RIPA and transcriptional activities and use coronavirus as a model virus capable of antagonizing IRF3-mediated innate immune responses. A thorough understanding of the cellular control of IRF3 and the mechanisms that viruses use to subvert this system is critical for developing novel therapies for virus-induced pathologies.

The interferon system is the first line of defense against virus infection. Recently, using a high-throughput genetic screen of a human interferon-stimulated gene short-hairpin RNA library, we identified a viral restriction factor, TDRD7 (Tudor domain–containing 7). TDRD7 inhibits the paramyxo-/pneumoviruses (e.g. Sendai virus and respiratory syncytial virus) by interfering with the virus-induced cellular autophagy pathway, which these viruses use for their replication. Here, we report that TDRD7 is a viral restriction factor against herpes simplex virus (HSV-1). Using knockdown, knockout, and ectopic expression systems, we demonstrate the anti–HSV-1 activity of TDRD7 in multiple human and mouse cell types. TDRD7 inhibited the virus-activated AMP-activated protein kinase (AMPK), which was essential for HSV-1 replication. Genetic ablation or chemical inhibition of AMPK activity suppressed HSV-1 replication in multiple human and mouse cells. Mechanistically, HSV-1 replication after viral entry depended on AMPK but not on its function in autophagy. The antiviral activity of TDRD7 depended on its ability to inhibit virus-activated AMPK. In summary, our results indicate that the newly identified viral restriction factor TDRD7 inhibits AMPK and thereby blocks HSV-1 replication independently of the autophagy pathway. These findings suggest that AMPK inhibition represents a potential strategy to manage HSV-1 infections.

Interferon (IFN) regulatory factor 3 (IRF3) is a transcription factor activated by phosphorylation in the cytoplasm of a virus-infected cell; by translocating to the nucleus, it induces transcription of IFN-β and other antiviral genes. We have previously reported IRF3 can also be activated, as a proapoptotic factor, by its linear polyubiquitination mediated by the RIG-I pathway. Both transcriptional and apoptotic functions of IRF3 contribute to its antiviral effect. Here, we report a nontranscriptional function of IRF3, namely, the repression of IRF3-mediated NF-κB activity (RIKA), which attenuated viral activation of NF-κB and the resultant inflammatory gene induction. In Irf3 −/− mice, consequently, Sendai virus infection caused enhanced inflammation in the lungs. Mechanistically, RIKA was mediated by the direct binding of IRF3 to the p65 subunit of NF-κB in the cytoplasm, which prevented its nuclear import. A mutant IRF3 defective in both the transcriptional and the apoptotic activities was active in RIKA and inhibited virus replication. Our results demonstrated IRF3 deployed a three-pronged attack on virus replication and the accompanying inflammation.

Virus-infected cells trigger a robust innate immune response and facilitate virus replication. Here, we review the role of autophagy in virus infection, focusing on both pro-viral and anti-viral host responses using a select group of viruses. Autophagy is a cellular degradation pathway operated at the basal level to maintain homeostasis and is induced by external stimuli for specific functions. The degradative function of autophagy is considered a cellular anti-viral immune response. However, autophagy is a double-edged sword in viral infection; viruses often benefit from it, and the infected cells can also use it to inhibit viral replication. In addition to viral regulation, autophagy pathway proteins also function in autophagy-independent manners to regulate immune responses. Since viruses have co-evolved with hosts, they have developed ways to evade the anti-viral autophagic responses of the cells. Some of these mechanisms are also covered in our review. Lastly, we conclude with the thought that autophagy can be targeted for therapeutic interventions against viral diseases.

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