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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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Signaling in the innate immune system prr signaling

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


Signaling in the innate immune system prr signaling

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


Pamps

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


Endocytic pattern recognition receptors

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.


Signaling pattern recognition receptors

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)


Signaling prrs found in the membranes of the endosomes phagolysosomes

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


Toll like receptors tlrs

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!"


Toll like receptors pattern recognition

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


The horseshoe structure of tlr3

The horseshoestructure of TLR3

TLR3 structureshowingattachedsugars (spheres) and internalstructures (wires, arrows, andhelixes)

GNU Free DocumentationLicense


Signaling in the innate immune system prr signaling

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


Tlr signaling

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


Tlr signaling1

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


Tlr related transcription factors

TLR relatedtranscription factors

  • Nuclear factor (NFB)

  • Activator protein 1 (AP-1)

  • Interferon regulatory factors (IRFs)

    to induce antibacterial and antiviral responses


Toll like receptor inhibitors

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


I nflammatory cytokines

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


Opsonins

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


Secreted prrs

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.


Complement receptors

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


Overview of complement receptor cr and toll like receptor signaling

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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