Since their initial discovery, an explosion of research carried out in the Toll-like receptor field has certainly established TLRs as the major sensory molecules of the innate immune system. The pivotal role these receptors play in detecting invading pathogens and initiating a host immune response to such foreign material is underlined by the fact that they are so widely conserved in mammals and insects. While the link between TLRs and the sensing of bacterial and fungal infection by host innate immune responses has been apparent since their initial discovery, an analogous association between TLRs and viruses has only come to light more recently. Nevertheless, a function for TLRs in sensing primary viral infection is now clear. In the same way that individual TLRs have been implicated in detecting distinct bacterial and fungal structural moieties, or pathogen associated molecular patterns (PAMPs) as they have become known, a similar picture is now emerging for the recognition of viral components by TLRs. A number of viral structural entities have been identified as targets for TLR recognition. Examples include viral single-stranded RNA which is sensed by both TLR7 and TLR8, double stranded RNA (TLR3), viral DNA (TLR9), as well as a number of specific viral structural proteins which have been shown to activate signal transduction through TLR2 and TLR4. The signalling pathways induced by different TLRs are determined by their adaptor molecule usage and as such myeloid differentiation factor 88 (MyD88) and TIR domain-containing adaptor inducing IFN-P (TRIF) represent two key adaptors which transduce signals on activation of TLRs in response to viral infection (see below).

The cascade of events which occurs following engagement of TLRs by viral components may be considered two-fold. Firstly, the ensuing signalling events culminate in the activation of an inflammatory response characterised by the production of a wide range of proinflammatory cytokines and chemokines such as TNF, IL-6, IL-8 and RANTES. Crucially, the activation of TLRs by viruses results in the production and release of type I interferons (IFN-a/p). These antiviral cytokines function specifically to inhibit viral replication and de novo synthesis of viral proteins, for exam-

Toll-like Receptors in Inflammation, edited by Luke A.J. O'Neill and Elizabeth Brint © 2006 Birkhäuser Verlag Basel/Switzerland ple, through the activation of PKR and 2'-5' oligoadenylate synthase. Thus, TLRs instigate an initial rapid response to viral infection in an attempt to limit viral spread within the host. A second critical function of TLR activation by viruses is the priming of the adaptive arm of the host immune response. This is not entirely separate from the IFN-inducing function of TLRs as the potent activation of cytotoxic T lymphocytes (CTLs) seen on triggering TLR signalling has been shown to be dependent on IFN-a/p at least for TLR3, 4, 7 and 9 [1]. CTL are potentially the most important protective component of host immunity to an array of viruses. Thus, the significance of TLRs in preventing virus-induced disease may lie in this cross-talk between the innate immune response and antigen-specific adaptive immunity.

Whether the outcome of the complex interplay between TLRs and viruses should favour the virus or the host is not always self-evident. TLR-mediated inflammation can, potentially, induce an antiviral state, thus preventing infection of target cells and subsequent viral spread within the host. This could then, of course, help to limit the horizontal transmission of the virus. On the other hand, it would seem that, in some cases, the severe inflammation occurring as a result of TLR activation by viral infection can contribute to the pathogenesis and severity of virus-induced disease. Teasing out these complex interactions between TLRs and viruses will potentially open up a myriad of therapeutic strategies for treating virus-associated and other diseases. These could range from the use of adjuvants to prime TLR-induced inflammatory responses, to the targeted inhibition of TLR-mediated inflammation in the case of some viral infections and auto-immune diseases.

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