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Signaling in the innate immune system PRR signaling

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Signaling in the innate immune system PRR signaling

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction Signaling in the innate immune systemPRR signaling

  3. PAMPs • The microbe-specificmoleculesthatarerecognizedby a givenPatternRecognition Receptor (PRR) arecalledPathogen-AssociatedMolecularPatterns(PAMPs): • Bacterialcarbohydrates (e.g. lipopolysaccharideor LPS mannose) • Nucleicacids (e.g. bacterialorviral DNA or RNA), • Bacterialpeptides (flagellin, ax21) • Peptidoglycans • Lipotechoicacids (fromGrampositivebacteria) • N-formylmethionine, lipoproteins and fungalglucans • EndogenousstresssignalsarecalledDAMPs (danger-associatedmolecularpatterns) and includeuricacid

  4. EndocyticPattern-RecognitionReceptors • Mannose receptors of phagocytesare C-type lectins bind mannose-rich glycans with mannose or fructose as the terminal sugar that are commonly found in microbial glycoproteins and glycolipids. • Scavenger receptors bind to bacterial cell wall components such as LPS, peptidoglyan and teichoic acids and stressed, infected, or injured cells. Scavenger receptors include CD36, CD68, and SRB-1. • Opsonin receptorsbind microbes to phagocytes. • N-formyl Met receptors bindN-formylmethionine, the first amino acid produced in bacterial proteins.

  5. SignalingPattern-RecognitionReceptors • Cellsurface /Extracellular TLRs: TLR1, TLR2, TLR4, TLR5, and TLR6 • SignalingPRRsfoundinthemembranes of theendosomes /phagolysosomes: TLR3, TLR7, TLR8, and TLR9 • SignalingPRRsfoundinthecytoplasm: NOD1, and 2 (CARD-containingproteins)

  6. SignalingPRRsfoundinthemembranes of theendosomes/phagolysosomes • TLR-3, 7 and 8bind single- or double-stranded viral RNA • TLR-9 binds unmethylated cytosine-guanine dinucleotide sequences (CpG DNA) • Most of the TLRs that bind to viral components trigger the synthesis of interferons that block viral replication within infected host cells

  7. Toll-likereceptors(TLRs) • Theyaresingle, membrane-spanning, non-catalyticreceptorsthatrecognizestructurallyconservedmoleculesderivedfrommicrobes • Theyreceivetheirnamefromtheirsimilaritytothe protein codedbythe Toll geneidentifiedinDrosophilain 1985 byChristianeNüsslein-Volhard. The geneinquestion, whenmutated, makesthe Drosophila flieslookunusual, or 'weird'. The researchersweresosurprisedthattheyspontaneouslyshouted out inGerman "Dasist ja toll!" whichtranslatesas "That´s wild!"

  8. Toll-likereceptors-patternrecognition Peptidoglycan (G+) Lipoprotein Lipoarabinomannan(Mycobacteria) LPS (Leptospira) LPS (Porphyromonas) GPI (Trypanosomacruzi) Yymosan(Yeast) Lipoteichoic acids (G+) RVS F protein LPS (G-) Unmethylated CpG DNA dsRNA Flagellin TLR1 TLR2 TLR2 TLR6 TLR3 CD14 TLR4 TLR5 TLR9 MD-2

  9. The horseshoestructure of TLR3 TLR3 structureshowingattachedsugars (spheres) and internalstructures (wires, arrows, andhelixes) GNU Free DocumentationLicense

  10. TLR types LPS dsRNA LBP TLR2 TLR4 MD2 TLR9 TLR7 TLR3 CD14 MDA-5 RIG-1 TBK1 IKKe IPS1 MyD88 MyD88 JAK2 PI3K p38 JNK mTOR MyD88 TRIF PKA TAK1 PKR MKKs lkB p50 p65

  11. TLR signaling • Induces potent innate immune responses that signal through adaptor molecules: • Myeloid differentiation factor 88 (MyD88) • Toll/interleukin (IL)-1 receptor (TIR) domain containing adaptor protein (TIRAP) • TIRdomain containing adaptor inducing interferon (IFN) (TRIF) • TRIF-related adaptor molecule (TRAM) to activate

  12. TLR signaling LBP TLR4 MD2 CD14 Plasmamembrane Cytoplasm TAB2 IRAK1 TAK1 MyD88 TRAF6 TRAP TRAM IRAK4 TRIF TBK1 RIP IKKe IKKs PI3K MAP3Ks MEK1/2 MKK3/6 IRF3 MKK4/7 IkB NFkB Akt ERK1/2 JNK p38 Nucleus NFkB AP-1 IRF3

  13. TLR relatedtranscription factors • Nuclear factor (NFB) • Activator protein 1 (AP-1) • Interferon regulatory factors (IRFs) to induce antibacterial and antiviral responses

  14. Toll-like receptor inhibitors LPS Polymixin B LBP TLR2 TLR4 MD2 OxPAPC CD14 dsRNA CLI095 TBK1 IKKe Chloroquine MyD88 MyD88 TLR9 TLR7 TLR3 RIG-1 MDA-5 JAK2 AG490 LY294002 IPS1 PI3K Wortmannin BX795 mTOR Rapamycin MyD88 TRIF PepinhMYD PepinhTRIF PKA TAK1 PKR H-89 2-Aminopurine PD98059 Bay11-7082 MKKs lkB p50 U0126 Celastrol p65 p38 JNK SB203580 SP600125

  15. Inflammatory cytokines • Interleukin-1 (IL-1) • Tumor necrosis factor-alpha (TNF-alpha) • Interleukin-12 (IL-12) • Chemokines such as interleukin-8 (IL-8), MCP-1, and RANTES

  16. Opsonins • Acute phase proteins like mannose-bindinglectin(MBL), C-reactive protein (CRP) • C3b C4b complement factors • Surfactant proteins in the alveoli SP-A and SP-D • The antibody molecule IgG can function as an opsonin

  17. SecretedPRRs • Complementreceptors • Collectins • Pentraxinproteinssuchasserumamyloid and C-reactive protein • Lipidtransferases • Peptidoglycanrecognitionproteins (PGRs) • LRR, XA21D • Oneveryimportantcollectin is mannan-bindinglectin(MBL), a major PRR of theinnateimmunesystemthatbindsto a widerange of bacteria, viruses, fungi and protozoa. MBL predominantlyrecognizescertainsugargroupsonthesurface of microorganismsbutalsobindsphospholipids, nucleicacids and non-glycosylatedproteins.

  18. Complementreceptors APC T cell CR1 Inhibits cell proliferation Expressed on <15% CR1 CR2 Antigenrecognition and uptake CR2 CR3 CR3 Unknown Expressed on <5% CR4 CR4 CRIg Pathogen recognition and/or clearance SIGNR1 Cytokinemodulation Expressed onactivation C3aR C3aR Modulation of TH1/TH2 commitment T-cell trafficking Upregulated by activation C5aR C5aR Antigen recognition and uptake C1qR C1qRP Cytokine modulation CD46 CD46 Activation/proliferation, cytokine modulation and lineage commitment Cytokine modulation and APC maturation CD55 CD55 CD59 CD59

  19. Overview of complement receptor (CR) and Toll-like receptor signaling Bacteria Viruses C3b C5 iC3b C1q C5a CR3 TLR C5aR gC1qR CD46 TLR4-induced IL-12 inhibited by posttranscriptional mechanism PI3K Erk1/2 IRF-1, IRF-8 IL-12p35 IL-12/IL-23p40 IL-23p19 IL-27p28 Nucleus

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