part of 10.2217/17460794.3.2.147 © 2008 Future Medicine Ltd ISSN 1746-0794 REVIEW Future Virol. (2008) 3(2), 147–156 147 Innate immune signaling pathways: lessons from vaccinia virus Tara Hurst & Andrew G Bowie † † Author for correspondence School of Biochemistry & Immunology, Trinity College Dublin, Dublin 2, Ireland Tel.: +35 318 962 435; Fax: +35 316 772 400; agbowie@tcd.ie Keywords: innate immunity, interferon, NF-κB, RIG-I-like receptors, signal transduction, Toll-like receptors, vaccinia virus, viral evasion In recent years there has been an avalanche of new data revealing how the innate immune system, using pattern recognition receptors, initially senses viruses. This leads to signaling pathways resulting in transcription factor activation, and subsequent induction of cytokines and interferons. Here we show how studying the immune evasion strategies of vaccinia virus, and elucidating the underlying molecular mechanisms of these strategies, has provided some important lessons as to how these pathways operate and how they are subverted by viruses. T he innate immune response involves the recog- nition of an array of common microbial mole- cules termed pathogen-associated molecular patterns (PAMPs) by a series of pattern recog- nition receptors (PRRs) [1]. In antiviral immu- nity, the PRRs recognize PAMPs that are either core components of the infecting virions or are produced in the cell during viral replication [2]. Surface glycoproteins, genomic nucleic acids (DNA, dsRNA and ssRNA) and nucleic acids produced during replication (viral mRNAs and dsRNA intermediates) initiate antiviral signaling [3]. Many antiviral pathways lead to the activa- tion of transcription factors, such as interferon regulatory factors (IRFs), particularly IRF3 and IRF7, as well as NF-κB and AP-1, which act together to induce type I interferons (IFNs) [4]. The early induction of type I IFNs is crucial in antiviral immunity, leading to the activation of cytotoxic cells and to the induction of antiviral signaling in neighboring uninfected cells [2]. Viruses have an inherent need to counteract antiviral signaling pathways in order to block IFN induction and hence replicate within cells. T herefore, it is not surprising that there is a plethora of viral proteins that inhibit or modu- late innate immune signaling pathways. Inter- estingly, there are also viral proteins that function to selectively activate immune signal- ing pathways that induce regulatory cytokines, thereby favoring viral replication by suppress- ing the immune response. Vaccinia virus (VACV) is a large, dsDNA virus that encodes numerous immunomodulatory proteins in its genome that target both the innate and adaptive immune systems (reviewed in [5]). By studying such viral proteins and determining how they act much can be learnt, not only about viral eva- sion, but also about the host immune response. T his review will describe some of the antiviral innate immune signaling pathways that VACV inhibits or activates, and presents some lessons learnt from such studies about the host innate immune response. Inhibition of Toll-like receptor signaling by VACV Toll-like receptors are important viral PRRs The finding that the VACV proteins A52 and A46 inhibit NF-κB activation by Toll-like receptors (T LRs) was early evidence that T LRs have an antiviral role [6–8]. T LRs are an impor- tant family of PRRs expressed on many cell types, including antigen-presenting cells such as dendritic cells (DCs) [9]. TLRs are type I trans- membrane proteins with an ectodomain com- posed of leucine-rich repeats [9]. One or more agonists have been identified for most T LRs. T he T LRs that recognize lipid-based PAMPs are TLR4, TLR1/2 and TLR2/6 [10], although TLR2 and TLR4 have also been found to be activated by viral proteins [11]. For example, TLR2 recognizes the hemaglutinin protein of measles virus, while T LR4 responds to the F protein from respiratory syncytial virus [11]. Human TLR5 and murine TLR11 recognize protein PAMPs, while microbial nucleic acids activate TLRs 3, 7, 8 and 9 [10]. The TLRs that respond to microbial nucleic acids are localized to the endosomes [9], and their signaling path- ways are shown in Figure 1 . dsRNA and its synthetic analogue poly(I:C) are detected by TLR3 [9], while TLR7 and TLR8 respond to viral ssRNA and related analogues [9], and T LR9 recognizes unmethylated CpG motifs from both viruses and bacteria [9]. D NA viruses have genomes that are rich in CpG motifs [12]. Acti- vation of TLRs leads to the induction of IFNs, proinflammatory cytokines and chemokines via signaling pathways [9].