PMID: 16027039, 11607032 The first described ligands for TLRs were of bacterial origin, such as lipopolysaccharide (for TLR4) or peptidoglycan (for TLR2), but since the discovery of double-stranded (ds)RNA as the ligand for TLR3 it has been recognized that TLRs also have a role in the host defense against viruses.

PMID: 16027039 On dsRNA binding, TLR3 recruits the TIR adaptor molecule TRIF, which induces signaling pathways leading to the activation of IRF3 and NF-kappaB, and the initiation of an apoptotic cascade. PMID: 16027039, 15767257, 15710891 Also, NS3?4a, a protease from HCV, besides targeting some as yet unknown component of the RIG-I pathway, has been described recently to cleave TRIF specifically, thereby abrogating TLR3 signaling.

PMID: 16027039, 14519765 However, its recruitment to TLR4 is mediated by an additional adaptor molecule, TRIF-related adaptor molecule (TRAM).

PMID: 16027039 TRIF is not a TLR3-specific adaptor molecule but is also involved in IRF3 activation by TLR4.

PMID: 16027039, 14679297, 12524442 However, TBK1 mediates both TLR4- and TLR3-induced IRF3 activation [30], so the observed differences between TLR3- and TLR4-induced IRF3 activation might be quantitative rather than qualitative. PMID: 16027039, 15210742, 15210743 RIG-I and TLR3 even seem to depend on the same kinases, IKK-i and TBK1, to phosphorylate IRF3.

PMID: 16027039, 14679297, 12524442 However, TBK1 mediates both TLR4- and TLR3-induced IRF3 activation [30], so the observed differences between TLR3- and TLR4-induced IRF3 activation might be quantitative rather than qualitative.

PMID: 16027039 TBK1 recruitment to the amino-terminal region of TRIF mediates IRF3 activation, which is important for the induction of type I interferons. PMID: 16027039, 12566418, 15767367 Whereas A46R, a TIR domain-containing protein, binds to TRIF directly and inhibits poly(I:C)-induced IRF3 activation, A52R potently blocks TLR3 signaling, leading to NF-kappaB activation. PMID: 16027039, 15210742, 15210743 RIG-I and TLR3 even seem to depend on the same kinases, IKK-i and TBK1, to phosphorylate IRF3.

PMID: 16027039 TBK1 recruitment to the amino-terminal region of TRIF mediates IRF3 activation, which is important for the induction of type I interferons. PMID: 16027039, 12646618 In addition, TLR3 engagement leads to a much stronger induction of type I IFNs than does TLR4 signaling

PMID: 16027039, 14530355, 16006187, 11101877 NF-kappaB activation was originally thought to be mediated by TRAF6 11 and 13 but it is now clear that it is at least partially mediated by RIP1, which interacts at the carboxy-terminal of TRIF.

PMID: 16027039, 14530355, 16006187, 11101877 NF-kappaB activation was originally thought to be mediated by TRAF6 11 and 13 but it is now clear that it is at least partially mediated by RIP1, which interacts at the carboxy-terminal of TRIF. PMID: 16027039 RIP3 blocks TRIF-induced NF-kappaB activation, and can also by itself induce apoptosis, similarly to RIP1. PMID: 16027039, 12566418, 15767367 Whereas A46R, a TIR domain-containing protein, binds to TRIF directly and inhibits poly(I:C)-induced IRF3 activation, A52R potently blocks TLR3 signaling, leading to NF-kappaB activation.

PMID: 16027039, 14530355, 16006187, 11101877 NF-kappaB activation was originally thought to be mediated by TRAF6 11 and 13 but it is now clear that it is at least partially mediated by RIP1, which interacts at the carboxy-terminal of TRIF.

PMID: 16027039, 11607032 The first described ligands for TLRs were of bacterial origin, such as lipopolysaccharide (for TLR4) or peptidoglycan (for TLR2), but since the discovery of double-stranded (ds)RNA as the ligand for TLR3 it has been recognized that TLRs also have a role in the host defense against viruses.

PMID: 16027039, 14530355, 16006187, 11101877 NF-kappaB activation was originally thought to be mediated by TRAF6 11 and 13 but it is now clear that it is at least partially mediated by RIP1, which interacts at the carboxy-terminal of TRIF. PMID: 16027039 RIP3 blocks TRIF-induced NF-kappaB activation, and can also by itself induce apoptosis, similarly to RIP1. PMID: 16027039, 12566418, 15767367 Whereas A46R, a TIR domain-containing protein, binds to TRIF directly and inhibits poly(I:C)-induced IRF3 activation, A52R potently blocks TLR3 signaling, leading to NF-kappaB activation.

PMID: 16027039 Ultimately, TLR3 activation leads to the production of proinflammatory cytokines, type I IFNs and the initiation of apoptosis.

PMID: 16027039, 15814722 RIP1 also links TRIF to the apoptotic cascade [26], which is further mediated by FADD and caspase-8.

PMID: 16027039, 15814722 RIP1 also links TRIF to the apoptotic cascade [26], which is further mediated by FADD and caspase-8. PMID: 16027039 RIP3 blocks TRIF-induced NF-kappaB activation, and can also by itself induce apoptosis, similarly to RIP1.

PMID: 16027039, 15814722 RIP1 also links TRIF to the apoptotic cascade [26], which is further mediated by FADD and caspase-8. PMID: 16027039 RIP3 blocks TRIF-induced NF-kappaB activation, and can also by itself induce apoptosis, similarly to RIP1.

PMID: 16027039 RIP3 blocks TRIF-induced NF-kappaB activation, and can also by itself induce apoptosis, similarly to RIP1.

PMID: 16027039 Ultimately, TLR3 activation leads to the production of proinflammatory cytokines, type I IFNs and the initiation of apoptosis.

PMID: 16027039 Ultimately, TLR3 activation leads to the production of proinflammatory cytokines, type I IFNs and the initiation of apoptosis.

PMID: 16027039, 14557267 Consistent with this, IFN-stimulated response element induction by TLR4, but not by TLR3, requires the NF-kappaB subunit p65.

PMID: 16027039, 15731229, 15579900 Apart from this somewhat specific case, it was demonstrated that cytokines are induced in a TLR3-dependent manner in bronchial epithelial cell lines, on infection with the ssRNA viruses respiratory syncytial virus or influenza, although no animal models were used to verify a role for TLR3 in vivo.

PMID: 16027039, 11607032 The first described ligands for TLRs were of bacterial origin, such as lipopolysaccharide (for TLR4) or peptidoglycan (for TLR2), but since the discovery of double-stranded (ds)RNA as the ligand for TLR3 it has been recognized that TLRs also have a role in the host defense against viruses.

PMID: 16027039 TRIF is not a TLR3-specific adaptor molecule but is also involved in IRF3 activation by TLR4. PMID: 16027039, 12566418, 15767367 Whereas A46R, a TIR domain-containing protein, binds to TRIF directly and inhibits poly(I:C)-induced IRF3 activation, A52R potently blocks TLR3 signaling, leading to NF-kappaB activation.

PMID: 16027039, 15731229 Interestingly, however, Rudd et al. found that respiratory syncytial virus-induced CXCL10 and CCL5 production, but not CXCL8 production or viral replication, were impaired in the absence of TLR3.

PMID: 16027039, 15731229 Interestingly, however, Rudd et al. found that respiratory syncytial virus-induced CXCL10 and CCL5 production, but not CXCL8 production or viral replication, were impaired in the absence of TLR3.

PMID: 16027039, 12900525, 14976261, 14976262 With the discovery that unmethylated viral CpG-DNA (from herpes simplex virus-2) can stimulate TLR9 [4] and the identification of ssRNA (from influenza virus and HIV-1) as the ligand for TLR7. PMID: 16027039, 15034168, 14993594, 12900525 TLR7 is involved in the response to the ssRNA viruses VSV and influenza [5], whereas TLR9 has a role in responding to the dsDNA viruses MCMV [6], herpes simplex virus-1 (HSV-1) and HSV-2.

PMID: 16027039, 12900525, 14976261, 14976262 With the discovery that unmethylated viral CpG-DNA (from herpes simplex virus-2) can stimulate TLR9 [4] and the identification of ssRNA (from influenza virus and HIV-1) as the ligand for TLR7. PMID: 16027039, 15034168, 14993594, 12900525 TLR7 is involved in the response to the ssRNA viruses VSV and influenza [5], whereas TLR9 has a role in responding to the dsDNA viruses MCMV [6], herpes simplex virus-1 (HSV-1) and HSV-2.

PMID: 16027039, 12773480 Before the discovery of TLR3, it was well known that cells detected viral dsRNA through dsRNA-dependent protein kinase (PKR), which, in response, inhibits host translation by phosphorylating the initiation factor, the alpha subunit of eukaryotic protein synthesis initiation factor 2, and, similar to TLR3, activates NF-kappaB.