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PMID: 17667934,12697090 Following the discovery of TLR4, TLR2 was found to be the receptor for components of the Gram-positive bacterial cell wall, recognizing triacyl lipopeptides in combination with TLR1, and diacyl lipopeptides in combination with TLR6.

PMID: 17667934,12697090 Following the discovery of TLR4, TLR2 was found to be the receptor for components of the Gram-positive bacterial cell wall, recognizing triacyl lipopeptides in combination with TLR1, and diacyl lipopeptides in combination with TLR6.

PMID: 17667934,11607032 TLR3 recognises doublestranded RNA

PMID: 17667934,17283206,11323673,11489966 TLR5 recognises bacterial flagellin

PMID: 17667934,14976262,11812998,11130078 TLR7/8 recognise single-stranded viral RNA, and TLR-9 recognises unmethylated CpG DNA motifs present in both viruses and bacteria

PMID: 17667934,14976262,11812998,11130078 TLR7/8 recognise single-stranded viral RNA, and TLR-9 recognises unmethylated CpG DNA motifs present in both viruses and bacteria

PMID: 17667934,14976262,11812998,11130078 TLR7/8 recognise single-stranded viral RNA, and TLR-9 recognises unmethylated CpG DNA motifs present in both viruses and bacteria

PMID: 17667934,11057907 TLR3 signals via the MyD88-independent pathway using the alternate adaptor protein TRIF

PMID: 17667934,16497588 TRIF interacts with tumour necrosis factor (TNF) receptor associated factor 3 (TRAF3) 3 to activate TRAF-family-member-associated NFkB activator (TANK)-binding kinase 1 (TBK1), and the non-canonical inhibitor of NFkB (IkappaB) kinase , IKKi

indirect

PMID: 17667934,16497588 TRIF interacts with tumour necrosis factor (TNF) receptor associated factor 3 (TRAF3) 3 to activate TRAF-family-member-associated NFkB activator (TANK)-binding kinase 1 (TBK1), and the non-canonical inhibitor of NFkB (IkB) kinase , IKKi

indirect

PMID: 17667934 These kinases directly phosphorylate interferon regulatory factor-3 (IRF-3). PMID: 17667934,17190786 TBK1/IKKi phosphorylate IRF-3 and IRF-7, inducing a type-1 IFN response. PMID: 17667934,15841462 Otsuka et al showed that NS3 binds TBK1 to act as a competitive inhibitor of the TBK1-IRF-3 interaction, to reduce IRF-3 activation and therefore downstream IFNb induction

PMID: 17667934 Phosphorylated IRF-3 forms a dimer before translocating to the nucleus, where it induces expression of IFNb.

indirect

PMID: 17667934,15665823 TRIF is also able to interact with receptor-interacting protein 1 and TRAF6 to induce a late phase proinflammatory cytokine response

PMID: 17667934,15665823 TRIF is also able to interact with receptor-interacting protein 1 and TRAF6 to induce a late phase proinflammatory cytokine response

PMID: 17667934,16497588 TLR4 uses the adaptor TRAM to recruit TRIF and induce a type-1 IFN response via the MyD88-independent pathway described above PMID: 17667934 Figure2

PMID: 17667934,16497588 TLR4 uses the adaptor TRAM to recruit TRIF and induce a type-1 IFN response via the MyD88-independent pathway described above PMID: 17667934 Figure2

PMID: 17667934,12447441 In contrast, TLR4 uses the coadaptor Mal to recruit MyD88 to its TIR domain

PMID: 17667934,12447441 In contrast, TLR4 uses the coadaptor Mal to recruit MyD88 to its TIR domain

indirect

PMID: 17667934,17457343,15928677 Stimulation of the MyD88-dependent pathway initiates a downstream signalling cascade involving sequential activation of primary and secondary kinases including the interleukin-1 receptor (IL-1R) associated kinases -4 and -1 (IRAK-4, and -1), TRAF6 and TGF-b-activated kinase (TAK1). PMID: 17667934 Figure2

indirect

PMID: 17667934,17457343,15928677 Stimulation of the MyD88-dependent pathway initiates a downstream signalling cascade involving sequential activation of primary and secondary kinases including the interleukin-1 receptor (IL-1R) associated kinases -4 and -1 (IRAK-4, and -1), TRAF6 and TGF-b-activated kinase (TAK1). PMID: 17667934 Figure2

indirect

PMID: 17667934,17457343,15928677 Stimulation of the MyD88-dependent pathway initiates a downstream signalling cascade involving sequential activation of primary and secondary kinases including the interleukin-1 receptor (IL-1R) associated kinases -4 and -1 (IRAK-4, and -1), TRAF6 and TGF-b-activated kinase (TAK1). PMID: 17667934 Figure2

indirect

PMID: 17667934,17457343,15928677 Stimulation of the MyD88-dependent pathway initiates a downstream signalling cascade involving sequential activation of primary and secondary kinases including the interleukin-1 receptor (IL-1R) associated kinases -4 and -1 (IRAK-4, and -1), TRAF6 and TGF-b-activated kinase (TAK1). PMID: 17667934 Figure2

inidirect

PMID: 17667934,15208624 Activated TAK1, in a complex with the TAK-1 binding proteins, TAB1 and TAB2, phosphorylates the IKK complex and the MAP kinases (JNK, ERK and p38), leading to activation of transcription factors nuclear factor-kappa B (NF-KappaB), and/or activating protein-1 (AP-1), respectively.

indirect

PMID: 17667934,15208624 Activated TAK1, in a complex with the TAK-1 binding proteins, TAB1 and TAB2, phosphorylates the IKK complex and the MAP kinases (JNK, ERK and p38), leading to activation of transcription factors nuclear factor-kappa B (NF-KappaB), and/or activating protein-1 (AP-1), respectively.

indirect

PMID: 17667934,15208624 Activated TAK1, in a complex with the TAK-1 binding proteins, TAB1 and TAB2, phosphorylates the IKK complex and the MAP kinases (JNK, ERK and p38), leading to activation of transcription factors nuclear factor-kappa B (NF-KappaB), and/or activating protein-1 (AP-1), respectively.

indirect

PMID: 17667934,15208624 Activated TAK1, in a complex with the TAK-1 binding proteins, TAB1 and TAB2, phosphorylates the IKK complex and the MAP kinases (JNK, ERK and p38), leading to activation of transcription factors nuclear factor-kappa B (NF-KappaB), and/or activating protein-1 (AP-1), respectively.

PMID: 17667934,15208624 Activated TAK1, in a complex with the TAK-1 binding proteins, TAB1 and TAB2, phosphorylates the IKK complex and the MAP kinases (JNK, ERK and p38), leading to activation of transcription factors nuclear factor-kappa B (NF-KappaB), and/or activating protein-1 (AP-1), respectively. PMID: 17667934,12566418 A52R inhibits NF-kB induction by multiple TLRs via interaction with IRAK2 and TRAF6

indirect

PMID: 17667934,15208624 Activated TAK1, in a complex with the TAK-1 binding proteins, TAB1 and TAB2, phosphorylates the IKK complex and the MAP kinases (JNK, ERK and p38), leading to activation of transcription factors nuclear factor-kappa B (NF-KappaB), and/or activating protein-1 (AP-1), respectively.

PMID: 17667934,15208624 Activated TAK1, in a complex with the TAK-1 binding proteins, TAB1 and TAB2, phosphorylates the IKK complex and the MAP kinases (JNK, ERK and p38), leading to activation of transcription factors nuclear factor-kappa B (NF-KappaB), and/or activating protein-1 (AP-1), respectively.

PMID: 17667934,15208624 Activated TAK1, in a complex with the TAK-1 binding proteins, TAB1 and TAB2, phosphorylates the IKK complex and the MAP kinases (JNK, ERK and p38), leading to activation of transcription factors nuclear factor-kappa B (NF-KappaB), and/or activating protein-1 (AP-1), respectively.

PMID: 17667934,16497588 In contrast, TLR7/8 and TLR9 are able to use MyD88 to induce expression of both proinflammatory cytokines and type-1 IFN

PMID: 17667934,16306936,16306937,16604075,15800576,15361868,16612387,16125763 Following nucleic acid recognition,MyD88 forms a signalling complex with IRAK-1, IRAK-4, TRAF6, TRAF3, IKKa and a precursor of osteopontin (OPN)

PMID: 17667934 The MyD88- IRAK-4- TRAF6 complex activates NF-KappaB and AP-1 as described above.

PMID: 17667934 The MyD88- IRAK-4- TRAF6 complex activates NF-KappaB and AP-1 as described above.

indirect

PMID: 17667934 In addition, the recruitment of IRAK-1, TRAF-3, IKKa and OPN allows TLR7/8 and TLR9 to activate IRF-7, which translocates to the nucleus to regulate the expression of type-1 IFN genes, especially IFNa

PMID: 17667934 In addition, the recruitment of IRAK-1, TRAF-3, IKKa and OPN allows TLR7/8 and TLR9 to activate IRF-7, which translocates to the nucleus to regulate the expression of type-1 IFN genes, especially IFNa

indirect

PMID: 17667934 In addition, the recruitment of IRAK-1, TRAF-3, IKKa and OPN allows TLR7/8 and TLR9 to activate IRF-7, which translocates to the nucleus to regulate the expression of type-1 IFN genes, especially IFNa

PMID: 17667934,15208624 It was recognized that TLR-independent mechanisms existed to detect intracellular viral infection, and in 2004 Yoneyama and colleagues identified RIG-I as a cytosolic sensor of dsRNA produced during viral replication, triggering a type-1 interferon and proinflammatory cytokine response

PMID: 17667934 MDA-5 was identified soon after as a second CARD-containing helicase PMID: 17667934 Figure 2

PMID: 17667934 Following dsRNA binding, RIG-I undergoes a conformational shift allowing self-association and CARD interaction with a downstream adaptor protein, IFN-b promoter stimulator (IPS-1).

PMID: 17667934 Following dsRNA binding, RIG-I undergoes a conformational shift allowing self-association and CARD interaction with a downstream adaptor protein, IFN-b promoter stimulator (IPS-1).

PMID: 17667934,16127453 Like RIG-I, MDA5 associates with IPS-1 via a CARD–CARD interaction following dsRNA binding

PMID: 17667934,16858409 IPS-1 interacts with TRAF3 via its non-CARD region to activate TBK-1 and IKKi

PMID: 17667934,16858409 IPS-1 interacts with TRAF3 via its non-CARD region to activate TBK-1 and IKKi

indirect

PMID: 17667934,16858409 IPS-1 interacts with TRAF3 via its non-CARD region to activate TBK-1 and IKKi

indirect

PMID: 17667934,16858409 IPS-1 interacts with TRAF3 via its non-CARD region to activate TBK-1 and IKKi

indirect

PMID: 17667934,17190786 TBK1/IKKi phosphorylate IRF-3 and IRF-7, inducing a type-1 IFN response.

indirect

PMID: 17667934,17190786 TBK1/IKKi phosphorylate IRF-3 and IRF-7, inducing a type-1 IFN response.

indirect

PMID: 17667934,17190786 TBK1/IKKi phosphorylate IRF-3 and IRF-7, inducing a type-1 IFN response.

PMID: 17667934,16127453 IPS-1 interacts with FADD, an adaptor involved in death receptor signalling via its death domain

PMID: 17667934,16127453 IPS-1 interacts with FADD, an adaptor involved in death receptor signalling via its death domain

PMID: 17667934,17190786 FADD forms a complex with caspase-10, and caspase-8; the caspase cleavage products produced are specifically involved in downstream NF-kB activation and proinflammatory cytokine production

PMID: 17667934,17190786 FADD forms a complex with caspase-10, and caspase-8; the caspase cleavage products produced are specifically involved in downstream NF-kB activation and proinflammatory cytokine production

PMID: 17667934,11607032 Poly(I:C), a synthetic dsRNA analogue, was first demonstrated to be a ligand for TLR3 by Alexopoulou and colleagues in 2001, inducing type-1 interferons and proinflammatory cytokines in a MyD88-independent manner

PMID: 17667934,11812998,12032557 TLR7 and 8 also recognize synthetic antiviral compounds, including imidazoquinolines (imiquimod and R848) and certain guanine nucleotide analogues (loxoribine).

PMID: 17667934,11812998,12032557 TLR7 and 8 also recognize synthetic antiviral compounds, including imidazoquinolines (imiquimod and R848) and certain guanine nucleotide analogues (loxoribine).

PMID: 17667934,11812998,12032557 TLR7 and 8 also recognize synthetic antiviral compounds, including imidazoquinolines (imiquimod and R848) and certain guanine nucleotide analogues (loxoribine).

PMID: 17667934,11812998,12032557 TLR7 and 8 also recognize synthetic antiviral compounds, including imidazoquinolines (imiquimod and R848) and certain guanine nucleotide analogues (loxoribine).

PMID: 17667934,11812998,12032557 TLR7 and 8 also recognize synthetic antiviral compounds, including imidazoquinolines (imiquimod and R848) and certain guanine nucleotide analogues (loxoribine).

PMID: 17667934,11812998,12032557 TLR7 and 8 also recognize synthetic antiviral compounds, including imidazoquinolines (imiquimod and R848) and certain guanine nucleotide analogues (loxoribine).

PMID: 17667934 The F protein of RSV activates TLR4

PMID: 17667934,17082626,14739339,12163593,15521019,12663765,16973959,17082589 TLR2 has been shown to be activated by a number of viruses or viral proteins, including the haemaglutinin protein (HA) of measles virus (MV), HSV-1, the core and NS3 proteins of hepatitis C virus (HCV), the envelope glycoproteins B and H of human CMV and vaccinia virus (VV).

PMID: 17667934,17082626,14739339,12163593,15521019,12663765,16973959,17082589 TLR2 has been shown to be activated by a number of viruses or viral proteins, including the haemaglutinin protein (HA) of measles virus (MV), HSV-1, the core and NS3 proteins of hepatitis C virus (HCV), the envelope glycoproteins B and H of human CMV and vaccinia virus (VV).

PMID: 17667934,17082626,14739339,12163593,15521019,12663765,16973959,17082589 TLR2 has been shown to be activated by a number of viruses or viral proteins, including the haemaglutinin protein (HA) of measles virus (MV), HSV-1, the core and NS3 proteins of hepatitis C virus (HCV), the envelope glycoproteins B and H of human CMV and vaccinia virus (VV).

PMID: 17667934,17082626,14739339,12163593,15521019,12663765,16973959,17082589 TLR2 has been shown to be activated by a number of viruses or viral proteins, including the haemaglutinin protein (HA) of measles virus (MV), HSV-1, the core and NS3 proteins of hepatitis C virus (HCV), the envelope glycoproteins B and H of human CMV and vaccinia virus (VV).

PMID: 17667934,17082626,14739339,12163593,15521019,12663765,16973959,17082589 TLR2 has been shown to be activated by a number of viruses or viral proteins, including the haemaglutinin protein (HA) of measles virus (MV), HSV-1, the core and NS3 proteins of hepatitis C virus (HCV), the envelope glycoproteins B and H of human CMV and vaccinia virus (VV).

PMID: 17667934,17082626,14739339,12163593,15521019,12663765,16973959,17082589 TLR2 has been shown to be activated by a number of viruses or viral proteins, including the haemaglutinin protein (HA) of measles virus (MV), HSV-1, the core and NS3 proteins of hepatitis C virus (HCV), the envelope glycoproteins B and H of human CMV and vaccinia virus (VV).

PMID: 17667934 When patient PBMCs were stimulated with the specific TLR2 ligand Pam-3-Cys, relative suppression of TNFa induction was noted in the HBeAg-positive group, confirming functional significance.

PMID: 17667934 When patient PBMCs were stimulated with the specific TLR2 ligand Pam-3-Cys, relative suppression of TNFa induction was noted in the HBeAg-positive group, confirming functional significance.

indirect

PMID: 17667934,17190786 FADD forms a complex with caspase-10, and caspase-8; the caspase cleavage products produced are specifically involved in downstream NF-kB activation and proinflammatory cytokine production PMID: 17667934,17049367,15563593 The V proteins of paramyxoviruses have been shown to interact with MDA5, but not RIG-I, to inhibit dsRNA-induced activation of IRF3 and NF-kB

indirect

PMID: 17667934,17190786 FADD forms a complex with caspase-10, and caspase-8; the caspase cleavage products produced are specifically involved in downstream NF-kB activation and proinflammatory cytokine production

indirect

PMID: 17667934,17190786 FADD forms a complex with caspase-10, and caspase-8; the caspase cleavage products produced are specifically involved in downstream NF-kB activation and proinflammatory cytokine production

indirect

PMID: 17667934,12163593 The proinflammatory response to the HA protein of measles leads to the upregulation of CD150, an entry receptor for MV, and therefore the HA-TLR2 interaction may contribute to MV spread and pathogenesis

PMID: 17667934,12566418 A52R inhibits NF-kB induction by multiple TLRs via interaction with IRAK2 and TRAF6

PMID: 17667934,15998638 Interestingly, the A52R-TRAF6 interaction has been shown to simultaneously activate the MAP kinase p38 to enhance TLR-induced IL-10 induction the immunoregulatory role of IL-10 supports that this may be another virulence mechanism.

indirect

indirect

indirect

indirect

PMID: 17667934,15998638 Interestingly, the A52R-TRAF6 interaction has been shown to simultaneously activate the MAP kinase p38 to enhance TLR-induced IL-10 induction the immunoregulatory role of IL-10 supports that this may be another virulence mechanism.

indirect

PMID: 17667934,15710891 NS3/4a was found to inhibit the dsRNA-TLR3 response by cleaving the adaptor TRIF between amino acids (aa) 372 and 373.

indirect

PMID: 17667934,16177806,15710891,15710892 NS3/4a also interfered with the cytoplasmic response to dsRNA, by cleaving IPS-1 at aa Cys- 508, the downstream adaptor of RIG-I. PMID: 17667934,16585524 The effect was able to be blocked using a specific pharmacological inhibitor of the NS3/4a protease

PMID: 17667934,15841462 Otsuka et al showed that NS3 binds TBK1 to act as a competitive inhibitor of the TBK1-IRF-3 interaction, to reduce IRF-3 activation and therefore downstream IFNb induction

indirect

PMID: 17667934 GBV-B encodes a similar NS3/4a protease, which has also been shown to disrupt RIG-I signalling by targeting IPS-1 for cleavage

PMID: 17667934,17438296 Yang et al found that the 3ABC precursor of the 3C(pro) cysteine protease of HAV was targeted to the mitochondrial membrane where it cleaved IPS-1, disrupting signalling activity

indirect

PMID: 17667934,17438296 Yang et al found that the 3ABC precursor of the 3C(pro) cysteine protease of HAV was targeted to the mitochondrial membrane where it cleaved IPS-1, disrupting signalling activity

PMID: 17667934,17049367,15563593 The V proteins of paramyxoviruses have been shown to interact with MDA5, but not RIG-I, to inhibit dsRNA-induced activation of IRF3 and NF-kB

indirect

PMID: 17667934,17049367,15563593 The V proteins of paramyxoviruses have been shown to interact with MDA5, but not RIG-I, to inhibit dsRNA-induced activation of IRF3 and NF-kB

PMID: 17667934,17079289 More recently it has been shown that NS1 also directly interacts with RIG-I to inhibit downstream activation of IRF-3.

indirect

PMID: 17667934,17079289 More recently it has been shown that NS1 also directly interacts with RIG-I to inhibit downstream activation of IRF-3.

indirect

PMID: 17667934 Figure2

PMID: 17667934 Figure2

PMID: 17667934 Figure2