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

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
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Tímea Berki and Ferenc Boldizsár
Signal transduction

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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

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• 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

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• 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)

• TLR-3, 7 and 8 bind single- or doublestranded 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

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• They are single, membrane-spanning, noncatalytic 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
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!"

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

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TLR3 structure showing attached sugars (spheres) and internal structures
(wires, arrows, and helixes)
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License

TÁMOP-4.1.2-08/1/A-2009-0011
TLR2
MyD88
LPS
CD14
LBP
MD2
TLR4
MyD88
JAK2
PI3K mTOR
TLR9 TLR7 TLR3
MyD88 TRIF p38
PKA
MKKs
JNK
TAK1 PKR l k B p50 p65 dsRNA
RIG-1 MDA-5
IPS1
IKK e TBK1

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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

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

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• Nuclear factor (NF k B)
• Activator protein 1 (AP-1)
• Interferon regulatory factors (IRFs) to induce antibacterial and antiviral responses

TLR2
LPS
LBP
MD2
TLR4
Polymixin B
OxPAPC
CD14
MyD88
CLI095
MyD88
Chloroquine
TLR9 TLR7 TLR3
JAK2 AG490
LY294002
Wortmannin
PI3K mTOR Rapamycin
MyD88 TRIF
PepinhMYD
H-89
PD98059
U0126
SB203580 p38
PKA
MKKs
JNK
TAK1 PKR lkB p50 p65
SP600125
TÁMOP-4.1.2-08/1/A-2009-0011 dsRNA
RIG-1 MDA-5
IPS1
IKKe TBK1 BX795
PepinhTRIF
2-Aminopurine
Bay11-7082
Celastrol

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• 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

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• 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

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• Complement receptors
• Collectins
• Pentraxin proteins such as serum amyloid and Creactive 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.

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

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Bacteria Viruses
C3b
C5 iC3b
C1q C5a
CR3 TLR C5aR gC1qR CD46
Nucleus
Erk1/2
IRF-1,
IRF-8
PI3K
TLR4-induced IL-12 inhibited by posttranscriptional mechanism
IL-12p35
IL-12/IL-23p40
IL-23p19
IL-27p28