Toll-like receptors

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 I st M.sc microbiology

2. INTRODUCTION 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. STRUCTURE AND FUNCTION OF TLR 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. TLR LIGANDS 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 TYPES 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- κ B 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. TLR SIGNALLING PATHWAY 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. 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 .

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

14. TLR ACTIVITIES 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

15. FUTURE TLR PROSPECTS 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

16. SUMMARY TLR INTRODUCTION STRUCTURE OF TLR LIGANDS OF TLR RECEPTOR TYPES SIGNALING PATHWAY ACTIVITIES AND FUTURE PROSPECTS

17. REFERENCES 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,

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