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TOLL-LIKE RECEPTORS

TOLL-LIKE RECEPTORS. Toll-like receptors & Host-Pathogen Interaction. O’Neill, Luke A.J. “Immunity’s Early-Warning System”. Scientific American, Jan (2005), 38-45. Microbe products recognized. Conserved amoung microbes Known as p athogen- a ssociated m olecular p atterns ( PAMPs )

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TOLL-LIKE RECEPTORS

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  1. TOLL-LIKE RECEPTORS

  2. Toll-like receptors & Host-Pathogen Interaction O’Neill, Luke A.J. “Immunity’s Early-Warning System”. Scientific American, Jan (2005), 38-45.

  3. Microbe products recognized • Conserved amoung microbes • Known as pathogen-associated molecular patterns (PAMPs) • PAMPs are recognized by plants as well as animals, meaning this innate response arose before the split • Only vertebrates have evolved an adaptive immune response

  4. Pattern Recognition Receptors (PRRs) • Toll-like receptors • Natural history, function and regulation • Mannose binding lectin (MBL) • C-reactive protein • Serum amyloid –P • Functions of PRRs: • Opsonization, activation ofcomplement and coagulation cascades, phagocytosis, activation of pro-inflammatory signaling pathways, apoptosis

  5. Nuesslein-Volhard: Drosophila Toll • Identified a protein she called “Toll” meaning “weird” • Helps the Drosophila embryo to differentiate its top from its bottom (Neural tube development) http://www.nature.com/genomics/papers/drosophila.html 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  6. Gay: Toll and Inner Part of Human IL-1R is Similar • Searching for proteins similar to Toll • Shows cytoplasmic domain of Toll related to that of hIL-1R • Identity extends for 135 aa • Didn’t make sense Why does a protein involved in human inflammation look like one involved in fly neural tube development? 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  7. Toll Molecular Structure IL-1R Toll (will become TLRs) Ig-like domain • Toll receptor has an extracellular region which contains leucine rich repeats motifs (LRRs) • Toll receptor has a cytoplasmic tail which contains a Toll interleukin-1 (IL-1) receptor (TIR) domain LRRs Box 1 TIR Domain Box 2 Box 3

  8. Lemaitre: Flies use Toll to Defend from Fungi • Infected Tl-deficient adult flies with Aspergillus fumigatus • All flies died after 2-3 days • Flies use Toll to defend from fungi • Thus, in Drosophila, Toll seems to be involved in embryonic development and adult immunity 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  9. Lemaitre: Flies use Toll to Defend from Fungi • Drosophila has no adaptive immune system • Therefore needs a rapid antimicrobial peptide response • Two distinct pathways to activate antimicrobial peptide genes in adults • Mutations in Toll pathway reduce survival after fungal infection 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  10. Survival rate of adult Drosophila infected with Aspergillus fumigatus in Toll-

  11. Medzhitov & Janeway: Human Toll Discovery • Ancient immune defence system based on the Toll signalling • In insect, IL-1 receptor and the Toll protein are only similar in the segments within the cell • They searched for human proteins that totally resemble to Toll 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  12. Medzhitov & Janeway: Human Toll Discovery • Alignment of the sequences of human and Drosophila Toll proteins • Homology over the entire length of the protein chains • hToll gene most strongly expressed in Spleen and PBL (peripheral blood leukocytes) 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  13. Rock: Identification of hTLR1-5 • Identified 5 human Tolls, which they called Toll like receptors (TLRs) • TLR4 same as Medzhitov’s human Toll • 4 complete - 1 partial hTLR • 3 Drosophila TLRs 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  14. Poltorak: TLR4 Activated by LPS • Normal mice die of sepsis after being injected with LPS • C3H/HeJ mice have defective response to LPS and survive • Missense mutation affecting the cytoplasmic domain of Tlr4 • Major breakthrough in the field of sepsis – molecular mechanism that underlies inflammation revealed 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  15. Takeuchi: TLR6 discovery • Murine TLR6 expression detected in spleen, thymus, ovary and lung • Alignment of a.a. sequence of cytoplasmic domains: TLR6 most similar to TLR1 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  16. Chuang (2000): hTLR 7, 8 and 9 • Reported the cloning and characterization of 3 hTLRs • Ectodomain with multiple LRRs • Cytoplasmic domain homologous to that of hIL-1R • Longer ectodomain (higher MW) than hTLR1-6 • mRNA expression: hTLR7 - lung, placenta and spleen hTLR8 – lung and PBL hTLR9 - spleen, lymph node, bone marrow and PBL 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  17. Chuang (2001): hTLR10 • Expression of hTLR10 in human tissues and cell lines • Isolation of cDNA encoding hTLR10 • Contains 811 aa, MW 94.6 kDA • Architecture of hTLR10 same as in hTLR1-9 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  18. Chuang: hTLR10 • Phylogenetic tree of hTLR: a.a. identity with hTLR1 (50%) and hTLR6 (49%) • Only 30% with hTLR2 and 25% with the remaining ones 1988 1989 1997 1998 1999 2000 1985 1991 1996 2001

  19. TLR Roles O’Neill, Luke A.J. “Immunity’s Early-Warning System”. Scientific American, Jan (2005), 38-45.

  20. TLR Cell Type Distribution

  21. Toll-Like Receptors and their Ligands

  22. Converging Pathways • Effects of signaling are cell specific • NF-B activation is the end result of TLR-signaling Beutler, Nature 2004

  23. H+ H+ H+ H+ H+ H+ H+ H+ TLR3 H+ TRIF H+ NF-B H+ H+ Interferon Pathway Inflammatory Cytokines NF-B TLR Signaling Pathways TLR2/TLR1 TLR2/TLR6TLR4 Cell membrane MAL MyD88 TRIF TRAM MAL MyD88 TLR3 TLR7 TLR8 TLR9 IRF3 Endosome TRIF MyD88 IRF7

  24. P P IRF-3 LBP sCD14 LPS MD-2 MD-2 p65 p50 p65 p50 p50 NF-kB p50 NF-kB P P NF-B IFN- MyD88 Dependent and Independent Pathways: Major Role in Phagocyte Response LPS TLR4 Cell membrane TLR4 MyD88-Dependent Signaling TLR4 MyD88-Independent Signaling MyD88 MAL TNF COX2 IL-18 Chemokines Chemokines: Rantes, IP-10 IFN NF-B

  25. LBP TOLLIP UBC13 MEKK3 MKK3 sCD14 MKK7 LPS p38 MD-2 MD-2 (-) IB JNK Proteasome UBV1A IB p65 p50 TAB2 TAK1 TNF COX2 IL-18 TAB1 NF-B LPS TLR4 MyD88-Dependent Signaling TLR4 Cell membrane MyD88 MAL IRAK4 IRAK1 IRAK2 TRAF6 IKK- IKK- IKK- Paz S., Nakhaei P,( 2005)

  26. LBP sCD14 LPS MD-2 MD-2 P IB IRF-3 IB P p65 p50 P P P P NF-B IFN- LPS TLR4 TLR4 MyD88-Independent Signaling Cell membrane TRAM TRIF TRAF6 IKK- Proteasome TBK1 IKK- IKK- IKK Late induction Paz S., Nakhaei P,( 2005)

  27. IB IRF-3 IRF-7 IB p65 p50 LPS dsRNA CpG DNA TLR4 ssRNA Cell membrane TRIF Tyk2 Jak1 TRAM Endosome STAT2 STAT1 ssRNA CpG DNA TBK1 TLR7/8 TLR9 STAT2 STAT1 IRF-9 IKK- MyD88 IKK- IKK- IRAK4 IRAK1 Proteasome TRAF6 IFN- IFN- NF-B IFN Regulation Inflammatory Cytokines Paz S., Nakhaei P,( 2005)

  28. TRAF6 IRAK-M SOCS1 (-) (-) IKK- MD-2 MD-2 (-) (-) IKK- IKK- IB UBV1A IB p65 p50 Proteasome NF-B ST2 SIGIRR Negative Regulation of TLR Signaling in Phagocytes TLR4 Cell membrane MAL MyD88 Cytoplasmic molecules: • IRAK-M(restricted to monocytes and macrophages) • SOCS1 (Supressor of cytokine signaling 1) • A20(TNFAIP3) Membrane bound molecules: • SIGIRR (single immunoglobulin IL-1R-related molecule) • ST2 IRAK4 IRAK1 UBC13 A20 TNF COX2 IL-18

  29. (-) Inflammatory Cytokines Phagocyte Sabotage: Evading TLR Signaling Yersinia LcrV Pseudomonas LPS • Changing the target:Camouflaging or directly modifying the molecules that trigger TLR signaling (ex: P. aeruginosa). • Crossing the wires:Interfering with downstream TLR-mediated signaling or to express TLR agonists • (ex: Y. pestis). • Sneaking through the back door: • Bacteria such as Shigella sp. and Listeria sp. express proteins that facilitate their invasion of macrophages. TLR2/TLR1 TLR2/TLR6TLR4 Cell membrane TRIF TRAM MAL MyD88 Cytosolic Listeria NF-B Nature Reviews Molecular Cell Biology4; 385-396 (2003);

  30. Leishmania-Induced Chemokine Expression LPS TLR4 MyD88 independent MyD88 IRF-3 (-) IRAK-1 SHP-1 TRAF6 ? IKKs IkB-NFkB NF-kB AP-1 Chemokines (MCP-1, MIP-1a/b, MIP-2) No NO No CD14 NO CD14 Chemokines (Rantes, IP-10, MCP-1, MIP-1a/b, MIP-2, Eotaxin) IFN-b

  31. Chemokines, linking innate and adaptive immunity

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