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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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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


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

  • 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


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.


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)


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-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-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 horseshoestructure of TLR3

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

GNU Free DocumentationLicense


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

  • 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 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 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

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


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

  • 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


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.


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

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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