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Protein Protein Interactions: The Inflammasome

Protein Protein Interactions: The Inflammasome. Mark D. Wewers, M.D. Davis Heart and Lung Research Institute. Outline of Presentation. Innate vs. Adaptive Immunity Focus on TLR and NLRs Pyrogens (endogenous and exogenous) Intracellular sensors/inflammasomes

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Protein Protein Interactions: The Inflammasome

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  1. Protein Protein Interactions:The Inflammasome Mark D. Wewers, M.D. Davis Heart and Lung Research Institute

  2. Outline of Presentation • Innate vs. Adaptive Immunity • Focus on TLR and NLRs • Pyrogens (endogenous and exogenous) • Intracellular sensors/inflammasomes • Example of intracellular pathogen • Example of population differences in pathogen responses (caspase-12)

  3. Time Line for Innate vs. Adaptive Immunity Cooper MD and Alder MN. Cell 124:815, 2006.

  4. INFECTION • Fever/Inflammation • ARDS • Multiple Organ Failure IL-1/TNF

  5. Shock and Poor Tissue Perfusion May Lead to Distal Gangrene

  6. Black Death 25% of population died

  7. Hippocrates 5th century B.C. Illness due to natural causes

  8. Guns Germs and Steel Hypothesis Jared Diamond

  9. Meningococcemia

  10. core polysaccharide bacterial membrane “O” antigen lipid A Components of lipopolysaccharide

  11. How can our defense repertoire cover the enormous diversity in pathogen challenges? • Innate host response: • Static defense system • Focus on immutable components of pathogens (e.g., cell wall component) • Acquired host response: • Creative ability to change with pathogen • Depends upon the acquisition of recombinase gene (RAG)

  12. LRR LRR TLR NB NLR TIR Extracellular sensors Intracellular sensors Innate Pathogen Sensors

  13. Family of TLR’s and Ligands Beutler et al.

  14. TLRs and their ligands Akira et al. Nature Reviews (Immunology):4:499, 2004.

  15. The Signaling Pathway of Toll-like Receptors Medzhitov R. NEJM 343:338,2000.

  16. Exogenous pyrogen induces endogenous pyrogen.

  17. exogenous endogenous Both Endogenous and ExogenousPyrogens converge at NFkB

  18. Figure 2-10 Innate versus Adaptive Immunity Characteristics

  19. Bridge to Adaptive Immunity Medzhitov R. NEJM 343:338,2000.

  20. News from the Genome Project that has expanded our understanding of the innate host response repertoire.

  21. Plant Immunity: Pathogen sensing without Tolls

  22. Dangl JL, Jones JDG. Nature 411:826, 2001.

  23. Guard Hypothesis NB-LRR protein dissociates due to pathogen NB-LRR protein binds target complex due to pathogen binding to complex Dangl, J. et al. NATURE | VOL 411 | 14 JUNE 2001

  24. Exogenous pyrogen induces endogenous pyrogen.

  25. CARD p20 p20 p20 p10 p10 p10 Caspase-1 (ICE) QACRG p45 N p20 p10 C Active ICE

  26. Caspase Recruitment Domains: CARDs

  27. CARD/PYD NBD LRR CATERPILLER: A Large Family of Mammalian Genes Containing CARD, Pyrin, Nucleotide-binding, and Leucine-Rich Repeat Domains Harton JA et al. J. Immunol. 169:4088, 2002.

  28. Inflammasome Concept NALP1 NBD LRR pyrin CARD CARD ASC 10kD 20kD caspase-5 20kD 10kD caspase-1

  29. Domain structure of CATERPILLERs Martinon, F et al. Mol.Cell 10:417-426, 2002.

  30. TLR b IKK complex g a * k a I B k k NF NF B B 100 ’ s of genes proteasome b including IL - 1 and TNF gene expression k k NF NF B B Toll like receptors and the Signalosome signalosome

  31. Toll-like receptors Cell Death and Differentiation (2006) 13, 816–825

  32. Sea Urchin’s Pathogen Sensors Rast,J.P. et al. Science 314:952, 2006.

  33. pyrin pyrin pyrin CARD CARD CARD CARD CARD CARD NBD NBD NBD NBD NBD LRR LRR LRR LRR LRR ASC NALP1 IPAF NOD1 NOD2 NALP3

  34. CARD domain pyrin domain ASC TLR inflammasome NOD-2 NALP-1 CASPASE-1 Caspase-5 proIL-1 IL-1 Martinon, F et al. Mol.Cell 10:417-426, 2002.

  35. ASC Multiprotein Complex Assembly requires ASC • ASC (apoptosis associated speck forming complex)

  36. ASC ASC Critical to IL-1 Processing Sarkar A et al. J.Immunol. 176:4979, 2006.

  37. Need for Intracellular Pathogen Sensors • Phagosome escape

  38. Francisella as Model of Inflammasome Activation F. novicida F. n. heat-killed F. n. + cytochalasin D E. coli Gavrilin MA, PNAS 103:141, 2006.

  39. Phagosome Escape Induces Inflammasome Assembly F.novicida proIL-1 phagosome IL-1

  40. F. novicida induces both mRNA and processing and release of IL-1 Gavrilin MA, PNAS 103:141, 2006.

  41. Toll like receptors and the Signalosome signalosome proIL-1

  42. CARD domain pyrin domain ASC TLR inflammasome 1 2 NALP-1 CASPASE-1 Caspase-5 proIL-1 IL-1

  43. Molecular Cell 25, 713–724, March 9, 2007

  44. Inflammasome structure

  45. What about Septic Shock?

  46. Figure 2-45 part 1 of 3

  47. ASC Caspase 1 and Sepsis TLR NOD-2 NALP-1 CASPASE-1 Caspase-5 proIL-1 IL-1

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