Toll-like Receptors
TLR 1,2, 6
Recognises lipid and carbs – lipoproteins, glycolipids, on gram
positive bacterial cell wall
"TLR2:TLR2" - homodimerization of TLR2, meaning that two TLR2
molecules pair up to form a functional receptor complex.
Ligands: peptidoglycan, lipoteichoic acid (LTA), and
mycobacterial lipoprotein from mycobacteria.
TLR1:TLR2
triacylated lipoproteins, M tuberculosis
TLR2:TLR6
diacylated lipoproteins and LTA.
TLR2:Dectin 1 - cooperative interaction between TLR2 and Dectin 1,
Beta-glucans, components of yeast cell walls.
These different pairings of TLR2 with either itself or with other
receptors like TLR1, TLR6, or Dectin 1 allow the immune system to
detect a wide range of microbial components.
TLR 4
Recognises LPS form gram negative bacteria
Also taxol (anti-tumour agent), HMBG1 (released by dying cells),
fibrinogen
May contribute to sepsis (hyperinflammatory response) – mice with
TLR4 knock out resistant to disease
TLR 5, 10
TLR 5 – flagellin from gram positive and gram negative bacteria
TLR 10 – influenza viruses by sensing viral rna-protein complex
, TLR3,7,8,9
All located in endosomes/lysosomes
3 – viral double stranded rna
7,8 – viral ssRNA (eg. Influenza)
9 – viral dna, bacterial dna with unmethylated CpG motif
All induce the type 1 IFN response – viral infection
Role of TLR in infectious disease
Autosomal recessive IRAK-4 deficiency: This deficiency leads to
a condition where patients' cells do not respond to ligands for TLR1-
6 and TLR9, nor do they respond well to the cytokines IL-1 and IL-
18. This results in a poor cytokine response when stimulated with
whole bacteria. IRAK-4 (Interleukin-1 Receptor-Associated Kinase 4)
is a kinase that plays an essential role in the TLR signaling pathway.
Increased susceptibility to infections: Patients with IRAK-4
deficiency are particularly susceptible to a narrow spectrum of
infections, especially from bacteria like Streptococcus
pneumoniae and Staphylococcus aureus, which are common
in early childhood.
Similar phenotype with MyD88 deficiency: Individuals
with a deficiency in MyD88 (Myeloid differentiation primary
response 88), another crucial adaptor protein in TLR signaling,
exhibit a similar susceptibility to infections, including those
caused by Pseudomonas aeruginosa.
Thus, it is not because of alterations to TLR/IRK signalling pathway
that lead to resistance to many microorganisms as an alternative
way can restore the function
Autosomal dominant tlr3 deficiency – increase susceptibility to
hse (herpes)
Tuberculosis
Mtb is spread by aerosol droplets which are inhaled into the
alveoli of the lungs
Alveolar macrophages phagocytose mycobacteria through
receptors
TLR 1,2, 6
Recognises lipid and carbs – lipoproteins, glycolipids, on gram
positive bacterial cell wall
"TLR2:TLR2" - homodimerization of TLR2, meaning that two TLR2
molecules pair up to form a functional receptor complex.
Ligands: peptidoglycan, lipoteichoic acid (LTA), and
mycobacterial lipoprotein from mycobacteria.
TLR1:TLR2
triacylated lipoproteins, M tuberculosis
TLR2:TLR6
diacylated lipoproteins and LTA.
TLR2:Dectin 1 - cooperative interaction between TLR2 and Dectin 1,
Beta-glucans, components of yeast cell walls.
These different pairings of TLR2 with either itself or with other
receptors like TLR1, TLR6, or Dectin 1 allow the immune system to
detect a wide range of microbial components.
TLR 4
Recognises LPS form gram negative bacteria
Also taxol (anti-tumour agent), HMBG1 (released by dying cells),
fibrinogen
May contribute to sepsis (hyperinflammatory response) – mice with
TLR4 knock out resistant to disease
TLR 5, 10
TLR 5 – flagellin from gram positive and gram negative bacteria
TLR 10 – influenza viruses by sensing viral rna-protein complex
, TLR3,7,8,9
All located in endosomes/lysosomes
3 – viral double stranded rna
7,8 – viral ssRNA (eg. Influenza)
9 – viral dna, bacterial dna with unmethylated CpG motif
All induce the type 1 IFN response – viral infection
Role of TLR in infectious disease
Autosomal recessive IRAK-4 deficiency: This deficiency leads to
a condition where patients' cells do not respond to ligands for TLR1-
6 and TLR9, nor do they respond well to the cytokines IL-1 and IL-
18. This results in a poor cytokine response when stimulated with
whole bacteria. IRAK-4 (Interleukin-1 Receptor-Associated Kinase 4)
is a kinase that plays an essential role in the TLR signaling pathway.
Increased susceptibility to infections: Patients with IRAK-4
deficiency are particularly susceptible to a narrow spectrum of
infections, especially from bacteria like Streptococcus
pneumoniae and Staphylococcus aureus, which are common
in early childhood.
Similar phenotype with MyD88 deficiency: Individuals
with a deficiency in MyD88 (Myeloid differentiation primary
response 88), another crucial adaptor protein in TLR signaling,
exhibit a similar susceptibility to infections, including those
caused by Pseudomonas aeruginosa.
Thus, it is not because of alterations to TLR/IRK signalling pathway
that lead to resistance to many microorganisms as an alternative
way can restore the function
Autosomal dominant tlr3 deficiency – increase susceptibility to
hse (herpes)
Tuberculosis
Mtb is spread by aerosol droplets which are inhaled into the
alveoli of the lungs
Alveolar macrophages phagocytose mycobacteria through
receptors
