Chapter 3 The Induced Responses of Innate Immunity

Transcription

1 Chapter 3 The Induced Responses of Innate Immunity

2 Pattern recognition by cells of the innate immune system

3 Pattern recognition by cells of the innate immune system 4 main pattern recognition receptors (PRR) free receptors in serum membrane-bound phagocytic receptors membrane-bound signaling receptors cytoplasmic signaling receptors

4 Pattern recognition by cells of the innate immune system After entering tissues, many pathogens are recognized, ingested, and killed by phagocytes Elie Metchnikoff ( )

5 Pattern recognition by cells of the innate immune system 3 major phagocytic cells Macrophages Neutrophils Dendritic cells (DC) - conventional DC - plasmacytoid DC

6 Pattern recognition by cells of the innate immune system 3 major phagocytic receptors C-type lectin - Dectin-1 - Mannose receptor (MR) Scavenger receptors anionic polymers, acetylated LDL, long-chain fatty acids Complement receptors

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8 Pattern recognition by cells of the G-protein-coupled receptors on phagocytes link microbe recognition with increased efficiency of intracellular killing fmet-leu-phe (fmlp) receptor - chemotaxis - ROS innate immune system

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12 Pattern recognition by cells of the innate immune system Pathogen recognition and tissue damage initiate an inflammatory response Essential roles of inflammation in combating infection Deliver additional effector cells and molecules Provide a physical barrier with microvascular coagulation Promote repair of injured tissue

13 4 types of changes in inflammatory responses Increase in vascular diameter - prostaglandin, leukotriene, platelet-activating factor Endothelial cell activation - chemokines, cytokines Increase in vascular permeability - bradykinin Clotting in microvessels - coagulation system

14 Increase in vascular diameter Endothelial cell activation Increase in vascular permeability Clotting in microvessels

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16 Pattern recognition by cells of the innate immune system Toll-like receptors represent an ancient pathogen-recognition system Receptor protein Toll in Drosophila melanogaster

17 Pattern recognition by cells of the innate immune system Mammalian Toll-like receptors are activated by many different pathogen-associated molecular patterns 10 TLRs in human (13 in mice) All TLRs have extracellular multiple leucine-rich repeat (LRR) and cytoplasmic Toll-IL-1 receptor (TIR) domain

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20 Salmonella typhi

21 Direct recognition of PAMP by TLR1 and TLR2

22 Pattern recognition by cells of the innate immune system TLR-4 recognizes bacterial lipopolysaccharide in association with the host accessory proteins MD- 2 and CD14 MD-2 correct trafficking and LPS recognition LPS-binding protein (LBP) transfer LPS to CD14 CD14

23 Pattern recognition by cells of the innate immune system TLR4 recognizes bacterial LPS by a mechanism that is partly direct and partly indirect

24 TLRs activate the transcription factors NF-kB, AP-1, and IRF to induce the expression of inflammatory cytokines and type I interferons Signaling by TLRs induces production of - inflammatory cytokines and chemokines - antimicrobial peptides - IFN- / TLR signaling engages several transcription factors - NF- B - AP-1 - IRF

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27 The Nobel Prize in Physiology or Medicine in 2011 Bruce A Beutler USA Defective LPS response in TLR4 mutant mice Science (1998) Jules A Hoffmann Luxembourg Toll-mediated anti-fungal defense in Drosophila Science (1999)

28 Pattern Recognition in Innate Immune System The NOD-like receptors act as intracellular sensors of bacterial infection NOD-like receptors (NLRs) - nucleotide-binding oliomerization domain (NOD) - LRR - caspase recruitment domain (CARD) NOD proteins - NOD1 senses ie-dap, breakdown product of PGN - NOD2 senses muramyl dipeptide of PGN

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31 Pattern Recognition in Innate Immune System The RIG-I-like helicases detect cytoplasmic viral RNAs and stimulate interferon production RIG-I senses unmodified 5 -triphosphate end of ssrna MDA-5 senses dsrna Sensing of viral RNAs by RIG-I and MDA-5 induces - type I interferon production - pro-inflammatory cytokines

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33 Pattern Recognition in Innate Immune System Activation of TLRs and NLRs triggers changes in gene expression in macrophages and dendritic cells that have far-reaching effects on the immune response

34 Activation of NF B by Toll pathway Cytokines Chemokines Costimulatory molecules - B7 (CD80, CD86)

35 Pattern Recognition in Innate Immune System TLR signaling shares many components with Toll signaling in Drosophila Toll itself is not a pattern recognition receptor Peptidoglycan-recognition proteins (PGRPs) Gram-negative binding proteins (GNBPs)

36 Drosophila Toll is activated as a result of a proteolytic cascade initiated by pathogen recognition

37 Pattern Recognition in Innate Immune System TLR and NOD genes have undergone extensive diversification in both invertebrates and some primitive chordates Sea urchin has TLR genes - more than 200 NLR genes