A short presentation on the structure, types and signaling pathways involved in Toll-like receptors. Based on research articles.

1. TOLL-LIKE
RECEPTORS
SHRUTHI K
18308019
IST M.SC MICROBIOLOGY

2. • Toll receptors in insects, mammals and plants are key players
that sense the invasion of pathogens. Toll-like receptors (TLRs)
in mammals have been established to detect specific
components of bacterial and fungal pathogens.
• TLR is a part of innate immune system and it facilitates
recognition of pathogens by the help of pathogen recognition
regions (PRR). It is present on sentinel cells like macrophages
and dendritic cells and on few non immune cells like Human
Choroidal Melanocytes.
• TLR recognizes certain Pathogen-Associated Molecular Patterns
(PAMP) present on the microorganisms and when the ligands
bind to the receptors to activate certain cytokines.

3. • Bacteria can’t mutate the PAMP region to protect itself from TLR
as it is integral for its structure. TLR is essential for activation of
phagocytes and APC.
• Upon ligand binding, TLR activates host defense genes. These
pathways are coupled with nuclear translocation of
transcriptional factors.
History:
• The history of TLRs began with the discovery of phagocytic cells
and IL-1 in 1940
• Homology between IL-1RI and drosophila Toll was found in 1991
by Janeway and colleagues and this led to the discovery of
human Toll in 1997.

4. • The TLR family now consists of
10 members (TLR1-TLR10).
The cytoplasmic portion of Toll-
like receptors shows high
similarity to that of the IL-1
receptor family, and is now
called the Toll/IL-1 receptor
(TIR) domain.
• The IL-1 receptors possess an
Ig-like domain, whereas Toll-
Like receptors bear leucine-rich
repeats (LRRs) in the
extracellular domain. FIGURE 1: ADAPTED FROM PDB

5. FIGURE 2: Schematic cartoon of Toll-like receptor signaling
Massari, Paola & Toussi, Deana. (2014). Immune Adjuvant
Effect of Molecularly-defined Toll-Like Receptor Ligands.
Vaccines. 2. 323-353. 10.3390/vaccines2020323.

6. • Various ligands can bind to
TLR and activate the
signaling pathway. These
ligands are parts of
pathogenic microbes.
• They are a part of superfamily
with 10 types of TLR to which
different ligands bind to.
• The ligands that bind can be
LPS, peptidoglycan, LTA,
flagellin, dsRNA, CpG DNA.
FIGURE 3: LIGAND BINDING TO TLR
Takeda, Kiyoshi & Akira, Shizuo.
(2003). Toll receptors and pathogen
resistance. Cellular microbiology. 5.
143-53. 10.1046/j.1462-
5822.2003.00264.x.

7. FIGURE 4: Adapted from Immunology, Roitt (2013)

8. • TLR 1,2,6 recognizes lipoteichoic acid from Gram positive
organisms and lipoarabinomannan from Mycobacterium .
• TLR 2 in specific recognizes Lipopolysaccharides and it
cooperates with TLR 1 and 6.
• Macrophages from TLR 6 deficient mice did not produce CD36
on its surface. Similarly they reacted with Triacyl lipopeptide
• TLR 1 deficient mice reacted with diacyl but not triacyl
lipopeptide. Thus TLR 1 and 6 associate with TLR 2 to
discriminate diacyl and triacyl lipopeptide.
TLR 3:
• It recognizes dsDNA produced during viral replication. Type 1
interferon is produced.

9. TLR 4:
• It is the LPS receptor and transduces its signals.
• LPS-LBP complex is formed and this is associated with
CD14 on macrophages.
• MD2, a secreted protein reacts with extracellular region of
TLR 4.
TLR 5:
• Flagellin in flagellated bacteria acts as a ligand to activate TLR 5.
TLR 7:
• It is used in the treatment of infectious diseases as its used as an
antiviral Imidazoquinolones that is against HPV.
TLR 9:
• It helps in the recognition of CpG DNA . CpG DNA recognizes
endosomes after non-specific uptake into cells.

10. • It is NOT A CELL-SURFACE RECEPTOR unlike others which
indicates a different mechanism.
TLR 10:
• It has an anti-inflammatory reactions unlike other TLR. It is very
helpful in suppressing cytokines.
• TLR 10 mechanism was found to suppress NF-κB and MAP
kinase signalling.
• It is found in spleen, lymph nodes, B cell surface but not on T cell
surface.
TLR 11:
• It is present on monocytes, macrophages and dendritic cells.
• When an infection of Toxoplasma gondii occurs profilin from it
acts as a ligand for TLR 11 to activate Dendritic cells to induce T
cell production.

11. My-D88 pathway
• In the TLR-mediated signalling pathways, MyD88, IRAKs, and
TRAF6 play critical roles.
• MyD88 is an adaptor protein which produces inflammatory
cytokines.
• There are four IRAK family members: IRAK-1, IRAK-2, IRAK-M
and IRAK-4.
• IRAK-4-deficient mice showed almost no inflammatory
responses to LPS, peptidoglycan, dsRNA and CpG DNA
indicating that it is an important link in the pathway.
• Ligation of a TLR promotes dimerization and results in the
recruitment of MyD88, which contains two domains: a C-terminal
Toll homology, and an N-terminal death domain.

12. When ligand binds TLR and TIR dimerization
occurs recruiting MyD88 adaptor.
IRAK is activated by auto-phosphorylation.
Activated IRAK then recruits TRAF6 that
ultimately leads to the activation of the IKK
complex.
The oligomerization of TRAF6 activates TAK-
1, a member of the MAP 3-kinase family and
this leads to the activation of the IkB kinases.
These kinases, in turn, phosphorylate IkB,
leading to its proteolytic degradation and the
translocates NF-kB to the nucleus

13. MyD88 independent pathway
• MyD88-independent activation of the LPS-TLR4 signalling
pathway is evident in several aspects.
• Dendritic cells from MyD88-deficient, but not from TLR4-
deficient, mice showed functional maturation in response to
LPS.
• Lipopolysaccharide stimulation induced caspase-1-dependent
cleavage of the IL-18 precursor into its mature form.
• Lipopolysaccharide stimulation of MyD88-deficient macrophages
led to the induction of several IFN-inducible genes.
• In addition to LPS, dsRNA induced activation of NF-kB in
MyD88-deficient mice. TLR 3 induces MyD88 independent
pathway and activates IRF3 and IFN-β.

14. FIGURE 5: Kiyoshi Takeda and Shizuo Akira.
Toll receptors and pathogen resistance,
Cellular Microbiology (2003) 5(3), 143–153

15. TLR protects against variety of diseases like
• TLR3- herpes simplex encephalitis
• TLR2- leprosy, Lyme disease, Tuberculosis, Colorectal cancer
• TLR5- Legionnaire’s disease, resistance to SLE
• TLR7- Antitumor and antiviral properties

16. • TLR agonists as Vaccine adjuvants
• TLR used in antiviral therapy
• Used to treat neurotoxic infection.
• Used to treat atherosclerosis,
• To treat Parkinson’s and alzheimer’s disease
• To treat multiple sclerosis and many more neurodegenrative
diseases

17. • TLR INTRODUCTION
• STRUCTURE OF TLR
• LIGANDS OF TLR
• RECEPTOR TYPES
• SIGNALING PATHWAY
• ACTIVITIES AND FUTURE PROSPECTS

18. • Akira S, Mammalian toll like receptors, Curr.opin
immunol- 2003;15:5-11
• Adreem A Ulevitch R.J 2000, Toll like receptors in
induction of innate immune receptors, Nature 406, 782-
787
• Roitt,Immunology 2013
• Pier, lyczak, wetzler Infection, Immunology and Immunity.
• Terry K. Meansa, Douglas T. Golenbockb, Matthew J.
Fenton, The biology of Toll-like receptors,