Future perspectives

A growing body of evidence suggests that TLRs do indeed have a significant part to play in antiviral host defence. Despite a huge surge in research into the multifaceted interactions between TLRs and viruses in recent years, it would appear that we are only scratching the surface of this complex area. Further research is required to elu cidate the precise role of TLRs in host immune responses to viral infection in vivo and moreover, to define the outcomes of the many complicated relationships between TLRs and viruses.

The exact role of TLRs in viral disease progression needs to be elucidated. The innate immune response to mCMV has been shown to involve both TLR3 and TLR9 [19]. Both the TLR3/TRIF and the TLR9/MyD88 pathways led to the production of type I IFN. However, mice lacking TLR9 died quickly after infection, while the absence of TLR3 did not significantly reduce survival. In another study, the absence of TLR3 did not alter viral pathogenesis or impair the generation of adaptive antiviral responses in infections with either VSV, LCMV, mCMV or reovirus [100]. TLR3-induced inflammatory responses to WNV infection contributed to viral compromising of the blood brain barrier and in doing so greatly exacerbated inflammation and encephalitis in the brain [64]. Thus, TLR3-deficient mice showed enhanced survival compared to wild-type animals administered with a lethal dose of the virus. Similarly, the observation that mice defective in TLR2 expression were protected from a lethal dose of HSV-1 while a normal TLR2 phe-notype led to lethal viral encephalitis [17] implies that virus-induced TLR-mediated inflammation can indeed be detrimental to the host. On the other hand, TLR4 expression in vivo promotes effective and efficient clearance of RSV, minimising disease progression [2]. The observation that mutations in human TLR4, previously linked to hyporesponsiveness to LPS and increased infection with Gram-negative bacteria [101, 102], are associated with severe RSV bronchiolitis in infants [10] suggests that TLR4 may be equally important in controlling RSV disease in humans. Thus, a systematic analysis of the overall outcome of each TLR/virus interaction will be necessary in order to clarify the importance of TLRs in protection against viral infection.

Crucially, the direct binding of any individual viral PAMP, of protein or nucleic acid origin, to a TLR remains to be examined in detail. A lot of information has emerged as to how two bacterial PAMPs, LPS and flagellin, directly interact with the TLR4 and TLR5 receptor complexes, respectively, but no such structural studies have been carried out for any of the viral PAMPs identified to date. A related issue is whether or not the responses elicited by a given TLR are the same for different activators (e.g., LPS and RSV F protein in the case of TLR4). The existence of co-receptors, or indeed upstream pattern recognition receptors that would mediate specific PAMP recognition, and then activate TLRs, is still a possibility.

The lessons to be learned from the intricacies of TLR/virus interactions are potentially invaluable from the point of view of the development of therapeutic strategies, not only for the treatment of virus-associated diseases but also for the treatment of a vast array of inflammatory disorders. Virally encoded immunomod-ulatory molecules specifically targeting TLR-mediated immunity, such as the VV-encoded A46R and A52R proteins or HCV-encoded NS3/4A could potentially be exploited to suppress inappropriate TLR signalling in a number of clinical contexts.

No doubt the number of such viral TLR antagonists available for therapeutic manipulation will grow in the coming years.

Conversely, artificial TLR activation could also be of therapeutic value. Local mucosal delivery of CpG oligodeoxynucleotides to the genital tracts protected mice from a lethal HSV-2 challenge, through inducing dramatic changes in the genital mucosa, the recruitment of innate immune cells and the inhibition of HSV-2 replication [103]. Thus, the induction of TLR9-mediated mucosal innate immunity could provide protection against HSV infection. Use of the innocuous baculovirus, AcNPV, as a viral vector for gene delivery to mammalian cells has the added advantage of an adjuvant effect induced by the virus to prime TLR9-mediated immunity [32]. Finally, viral-TLR interactions have recently been suggested to be beneficial in cancer immunotherapy. In an established mouse model, vaccinia and adenoviral vectors could break CD8+ tolerance in the presence of regulatory T cells, while other cell-based vaccines could not, due to persistent virally induced TLR activation [104]. In conclusion, the potential rewards to be reaped from thoroughly understanding the complicated interactions between TLRs and viruses are boundless.

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