Trends in Molecular Medicine
Interferon gene regulation: not all roads lead to Tolls
Section snippets
Key breakthroughs in interferon gene regulation and antiviral sensing
Successful host defense against virus infection relies on early detection followed by the rapid production of type I interferons (IFNs), including multiple IFN-αs and IFN-βs [1]. We now understand in great detail how IFN-α and -β signal and elicit antiviral responses. By contrast, until recently, the knowledge of how viruses are detected during infection and how type I IFN genes are induced was limited. Several key discoveries have now been made which greatly increase the understanding of these
IFN gene regulation: a brief introduction
Transcriptional activation of the IFN-β gene requires assembly of a multiprotein complex, the enhanceosome, which consists of activating transcription factor (ATF)2 and c-Jun, IRF3 and NF-κB [14]. This review focuses primarily on IRF3 and related family members. In resting cells, IRF3 resides in the cytoplasm [15]. Virus infection results in its signal-dependent phosphorylation, dimerization and interaction with the co-activator proteins CBP and p300 16, 17. This IRF3-containing complex then
TRIF-dependent IRF3 signaling
Our best understanding of IFN gene regulation comes from studies on TLR3 and TLR4 signaling. Lipopolysaccharide (LPS), via TLR4, triggers the nuclear translocation and DNA binding of IRF3 [25] and subsequent induction of IFN-β and IFN-stimulated genes 26, 27. This IRF3 response is crucial for protection against endotoxic shock in vivo [28]. TLR3 signaling in response to the dsRNA mimetic polyinosinic–polycytidylic acid [poly (I-C)] can also activate IRF3 29, 30, 31, a process mediated solely by
IFN gene induction in pDCs
Neither TLR3 nor TLR4 are expressed on pDCs; therefore, these pathways cannot account for the vast production of IFN in these cells. TLR expression by human and mouse pDCs is restricted to TLR7 and TLR9 [43], making them highly specialized for the detection of viral nucleic acids. As a consequence, they produce large quantities of IFN-α and IFN-β in response to purified ligands, including imidazoquinolines [44] and ssRNA 5, 45, for TLR7 5, 45, 46 or CpG oligonucleotides (CpG-ODNs), as well as
IRF7: the master regulator of IFN responses
Another key paper by Honda et al. [12] has highlighted the importance of IRF7 in the control of IFN-α and IFN-β subtypes. Using mice deficient in IRF7, the authors have shown that IRF7 is essential for the induction of IFN-α and -β genes via the MyD88-dependent TLR7 and 9 pathway. IRF7-deficient pDCs fail to induce IFN-α and IFN-β in response to purified TLR ligands, such as CpG-ODNs, ssRNA or HSV-1. Consistent with the earlier in vitro studies by Schoenemeyer et al. [51], Honda et al. [52] and
Distinct and essential roles of IRF5 in innate immune signaling
In contrast to IRF3 and IRF7, which are activated by most viruses, the activation of IRF5 seems to be much more restricted [70]. Only certain viruses, including Newcastle disease virus (NDV), VSV and HSV, have been shown to activate IRF5, whereas others such as SV or dsRNA [poly (I-C)], which activate IRF3 and IRF7, do not activate IRF5 [71]. These observations suggest that IRF5 is activated by signaling mechanisms distinct from those acting on IRF3. Schoenemeyer et al. [51] have shown that,
Importance of TLRs in antiviral defense in vivo
Although it is clear that TLR3, TLR7, TLR8 and TLR9 recognize nucleic acid structures to elicit a type I IFN-α and IFN-β response, particularly in pDCs in vitro, the relevance of TLRs in the in vivo response to virus infection is still in question. Findings from the studies by Krug et al. [49] and Hochrein et al. [74] were the first to show no major changes in morbidity or mortality when TLR7- or TLR9-deficient mice were infected with influenza or HSV in vivo. Although the TLR9–MyD88 pathway is
TLR-independent IFN gene induction: discovery of RNA helicases
Because the relevance of TLRs in the in vivo response to infection is unclear, the search for additional antiviral sensors has found considerable momentum. There is now overwhelming evidence to support the idea that cytoplasmic PRRs exist which sense virus infection. Various groups have indicated the importance of TLR-independent pathways in regulating antiviral responses in vivo 45, 46, 47, 49, 74, 78, 82. The double-stranded RNA-activated protein kinase R (PKR) was the first of such
Concluding remarks
The understanding of innate antiviral immunity has increased dramatically as a result of the discoveries discussed herein. However, many unanswered questions remain (Box 1). The key outstanding issues relate to how the two disparate sensing systems signal to IFN genes, and the functional importance of both systems in vivo. Continued interest in these crucial issues will probably add to this understanding. Defining these mechanisms in great detail will be important for enabling the design of
Acknowledgements
We thank Simon Rothenfusser, Nadege Goutagny, Egil Lien and Neal Silvermann for critically reading the manuscript.
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