TLR7 and TLR8

TLR7 and 8 are the most recent family members to be implicated in responding to viral PAMPs. Originally, two imidazoquinoline compounds termed imiquimod and resiquimod (or R-848), that were known to have potent antiviral properties, were shown to activate murine macrophages in a MyD88- and TLR7-dependent manner [33]. It was subsequently shown that human TLR7 or TLR8, but not murine TLR8, could also confer cells with responsiveness to R-848 [34]. Several guano-sine analogues were then shown to mediate cellular activation via TLR7, in a process requiring endosomal maturation [35]. These initial studies on TLR7 and TLR8, together with the observation that G- and U- rich ssRNA oligonucleotides derived from HIV-1 stimulate DCs and macrophages to secrete IFN-a and proin-flammatory cytokines, led Heil et al. to show that recognition of GU-rich ssRNA was mediated by human TLR8 and murine TLR7 [36]. In addition, Diebold et al. showed that the production of large amounts of IFN-a by pDCs in response to wild-type influenza virus required endosomal recognition of influenza genomic RNA and signalling via murine TLR7 and MyD88 [37]. Further, this study showed that ssRNA molecules of non-viral origin (such as polyU) also induced TLR7-dependent production of inflammatory cytokines. In corroboration with these studies, Lund et al. demonstrated that as well as recognising influenza, TLR7 was required for pDC and B cell responses to another ssRNA virus, vesicular stomatitis virus (VSV) [38].

Together, TLR7, 8 and 9 form a functional subgroup within the TLR family that recognises viral PAMPs in endosomal or lysosomal compartments [36]. Thus, these TLRs are likely to be important for the detection of viruses which gain entry into the cell via endocytosis. For example, an ssRNA virus would reach the endosome through receptor-mediated uptake of a viral particle. There is evidence accumulating that, like TLR3 [39], these TLRs can respond to 'self' nucleic acid, which has been found to be immunostimulatory and may act as a 'danger signal', depending on its compartmentalisation [36, 37]. Hence, it may be more correct to think of TLR7, 8 and 9 as detecting the abnormal localisation of nucleic acid rather than structures or motifs absent from the host [37]. Overall it appears that cell surface TLR2 and TLR4 may recognise viral glycoproteins present on virions, while intra-cellular TLR3, TLR7, TLR8 and TLR9 may detect naked viral nucleic acid. Hence, there is ample evidence that TLRs have an important role in viral PAMP-induced gene induction which leads to activation of host innate immune responses.

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