2. First line of defense – innate immunity.
Ability to discriminate between self and
foreign pathogen relies on TLRs.
Discovered in Drosophila melanogaster as a
receptor for establishing dorsoventral polarity
during embryogenesis and component of
innate immunity in adult flies.
TLRs : first PRR to be identified .
Recognize different features (PAMPs) of
bacteria, viruses and other microbes.
3. TLRs are type I transmembrane proteins having:
• Ectodomain :amino terminal domain composed
of repeated motifs rich in leucine and known as
lecine rich repeats(LRRs).
• Transmembrane region
• Cytosolic domain: called as Toll/Interleukin I
receptor (TIR) domain.
TIR domain has 3 regions, highly conserved
among all family members, called boxes 1,2 in
and 3. these serve as binding site for intra
cellular proteins that participate in signalling
pathway.
4.
5. TLRs are expressed on cell surface and within
intracellular vesicles( ER, endosomes, lysosomes
etc.)
TLRs on cell surface recognize components of
microbial membrane while those expressed
within intracellular vesicles recognize foreign
nucleic acids.
Protein PRAT4A regulates exit of TLR1,
TLR2,TLR4, TLR7 and TLR9 from ER to respective
places.
Gp96 – ER resident heat shock protein 90 family
acts as chaperone for most TLRs .
6.
7.
8. TLR1, TLR2 and TLR6
Structurally related.
TLR2 recognizes:
Lipoproteins from various pathogens
• Peptidoglycan and techoic acid (Gram + ve
bacteria)
• Lipoarabinomanan (mycobacterium)
• Glycophosphatidyl inositol (Trypanosoma cruzi).
• Zymosan (fungi)
• Glycolipids (Treponema)
9. TLR1, TLR2 and TLR6
Heterodimer of TLR2 and TLR6 recognize
diacyl lipopeptides from mycoplasma.
Heterodimer of TLR2 and TLR1 recognize
triacyl lipopeptides from Gram –ve bacteria.
TLR2 and Dectin1( lectin family receptor)
recognize β-glucan (component of fungal cell
wall)
10. TLR3
Recognizes:
Genomic RNA from dsRNA virus (reovirus).
dsRNA (Influenza A, West Nile virus)
dsDNA (Herpes Simplex Virus)
TLR4
Essential for LPS recognition
LPS binds to soluble LPS binding protein
(LBP), then LPS transferred to CD14 and
finally TLR4 is activated.
11. TLR4
Also recognizes endogenous ligands such as:
Heat shock protein ( HSP 60 and 70)
Extra domain A of fibronectin, heparan
sulfate and fibrinogen.
Heterodimer of TLR4 and TLR6 enhances the
activity of TLR4 while its dimerisation with
TLR1 inhibits its activity.
12. TLR5
Recognize flagellin
Expressed where?
Mucosal surface of intestinal epithelial cells
Epithelial cells of lungs.
TLR7 and TLR8
Recognize imidazoquinoline (anti-viral
compound).
TLR8 active in humans not in mouse.
Also recognize nucleoside guanosine or uridine
rich ssRNA from viruses such as HIV and
Influenza virus.
13. TLR9
• Receptor for CpGDNA
• Bacterial DNA has unmethylated CpG motifs.
TLR11
• Active in mouse.
• Expressed in urinary bladdedr epithelial cells.
• Recognizes uropathogenic bacteria.