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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen

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(1)

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(2)

SIGNALING IN THE INNATE IMMUNE

SYSTEM PRR SIGNALING

Tímea Berki and Ferenc Boldizsár Signal transduction

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(3)

PAMPs

The microbe-specific molecules that are recognized by a given Pattern Recognition Receptor (PRR) are called Pathogen-

Associated Molecular Patterns (PAMPs):

• Bacterial carbohydrates (e.g. lipopolysaccharide or LPS mannose)

• Nucleic acids (e.g. bacterial or viral DNA or RNA),

• Bacterial peptides (flagellin, ax21)

• Peptidoglycans

• Lipotechoic acids (from Gram positive bacteria)

• N-formylmethionine, lipoproteins and fungal glucans

• Endogenous stress signals are called DAMPs (danger- associated molecular patterns) and include uric acid

(4)

Endocytic Pattern-Recognition Receptors

• Mannose receptors of phagocytes are 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 receptors bind microbes to phagocytes.

• N-formyl Met receptors bind N-formyl methionine, the first amino acid produced in bacterial proteins.

(5)

Signaling Pattern-Recognition Receptors

• Cell surface /Extracellular TLRs: TLR1, TLR2, TLR4, TLR5, and TLR6

• Signaling PRRs found in the membranes of the endosomes /phagolysosomes: TLR3, TLR7, TLR8, and TLR9

• Signaling PRRs found in the cytoplasm: NOD1, and 2 (CARD-containing proteins)

(6)

Signaling PRRs found in the membranes of the endosomes/phagolysosomes

• TLR-3, 7 and 8 bind 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-like receptors (TLRs)

• They are single, membrane-spanning, non-catalytic

receptors that recognize structurally conserved molecules derived from microbes

• They receive their name from their similarity to the protein coded by the Toll gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard. The gene in question, when mutated, makes the Drosophila flies look unusual, or 'weird'.

The researchers were so surprised that they spontaneously shouted out in German "Das ist ja toll!" which translates as

"That´s wild!"

(8)

Toll-like receptors-pattern recognition

Peptidoglycan (G+) Lipoprotein

Lipoarabinomannan (Mycobacteria) LPS (Leptospira)

LPS (Porphyromonas) GPI (Trypanosoma cruzi)

Yymosan (Yeast) dsRNA Flagellin

Unmethylated CpG DNA

TLR2

TLR1 TLR2 TLR6 TLR3 TLR5 TLR9

Lipoteichoic acids (G+) RVS F protein

LPS (G-)

TLR4 CD14 MD-2

(9)

The horseshoe structure of TLR3

TLR3 structure showing attached

sugars (spheres) and internal structures

(wires, arrows, and helixes)

GNU Free Documentation License

(10)

MyD88 TRIF TLR3 TLR7

TLR2

PKA TAK1 PKR

p38 JNK

MKKs lkB

p50 p65 MyD88

LPS

TLR4

MyD88 MD2 LBP

dsRNA

TBK1 IKKe

MDA-5 RIG-1

IPS1 TLR9

JAK2

mTOR PI3K CD14

TLR types

(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)

• TIR domain containing adaptor inducing interferon (IFN) (TRIF)

• TRIF-related adaptor molecule (TRAM) to activate

(12)

TLR signaling

TAB2

TLR4 MD2

LBP

TRAF6

TRIF TBK1 IRAK1

IRAK4 RIP

PI3K

Akt ERK1/2 MEK1/2

p38 MKK3/6 MAP3Ks

JNK MKK4/7

AP-1 TAK1

TRAP TRAM

IRF3

IRF3 IKKs

IkB NFkB

NFkB

MyD88

IKKe CD14

Nucleus Cytoplasm Plasma membrane

(13)

TLR related transcription factors

• Nuclear factor (NFkB)

• Activator protein 1 (AP-1)

• Interferon regulatory factors (IRFs)

to induce antibacterial and antiviral responses

(14)

Toll-like receptor inhibitors

MyD88 TRIF

TLR3 TLR7

TLR2

PKA

SP600125 SB203580

U0126 PD98059 H-89

Celastrol Bay11-7082 2-Aminopurine PepinhTRIF PepinhMYD

TAK1 PKR

p38 JNK

MKKs lkB

p50 p65 MyD88

Polymixin B

CLI095 LPS

TLR4

MyD88 MD2 LBP

dsRNA

BX795 TBK1

IKKe

MDA-5 RIG-1

IPS1 TLR9

Chloroquine

JAK2

Wortmannin

Rapamycin LY294002

AG490

mTOR PI3K CD14

OxPAPC

(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-binding lectin (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)

Secreted PRRs

• Complement receptors

• Collectins

• Pentraxin proteins such as serum amyloid and C-reactive protein

• Lipid transferases

• Peptidoglycan recognition proteins (PGRs)

• LRR, XA21D

• One very important collectin is mannan-binding lectin (MBL), a major PRR of the innate immune system that binds to a wide

range of bacteria, viruses, fungi and protozoa. MBL predominantly recognizes certain sugar groups on the surface of

microorganisms but also binds phospholipids, nucleic acids and non-glycosylated proteins.

(18)

Complement receptors

CR1 CR2 CR3 CR4

CR2 CR3 CR4 CRIg

SIGNR1 C3aR C5aR C1qR

CD46 CD55 CD59

C3aR

C5aR

C1qRP Antigen recognition

and uptake

Pathogen recognition and/or clearance

Modulation of TH1/TH2 commitment Antigen recognition and uptake

Cytokine modulation and APC maturation

CR1 Inhibits cell proliferation Expressed on <15%

Unknown

Expressed on <5%

Cytokine modulation Expressed on activation T-cell trafficking

Upregulated by activation

Cytokine modulation

CD46 CD55 CD59

Activation/proliferation, cytokine modulation and lineage commitment

APC T cell

(19)

Overview of complement receptor

(CR) and Toll-like receptor signaling

TLR

CR3 C5aR

C3b

gC1qR C1q

CD46 iC3b

C5

Bacteria Viruses

Erk1/2 PI3K

TLR4-induced IL-12 inhibited by posttranscriptional mechanism

Nucleus

IL-12p35 IL-12/IL-23p40 IL-23p19 IL-27p28 IRF-1,

IRF-8

C5a

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