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Toll-Like Receptors (TLR) In Fish

Biraj Bikash Sharma* and Gadadhar Dash

Department of Aquatic Animal Health

Faculty of Fishery Sciences, West Bengal University of Animal and Fishery Sciences

Kolkata- 700094, West Bengal, India

*Corresponding author: birajbikash@gmail.com



Introduction

Toll-like Receptors (TLR) are broadly expressed as a class of protein that have a principle role in the innate immune system. They are sometimes considered to have a dual functional position in an association with the digestive system. These are a single membrane spanning, non catalytic receptors simply termed as 'Toll' in insects and TLR in case of higher vertebrates. Moreover, these are type I transmembrane proteins distinguished by an extracellular domain containing Leucine-Rich Repeats (LRRs) and a cytoplasmic tail region called the Toll/IL-1 Receptor (TIR) domain. Toll gene was first identified in the Drosophila fly in 1985 by Christiane Nusslein Volhard. However, the most outstanding role is established in the case of the innate immune system. In the immunological study the fishes are considered as a crossroad between the innate and adaptive immune system. They are the first to evolve to continue from adaptive to innate immune system.

TLR recognizes the Pathogen-Associated Molecular Patterns (PAMP) and found to have a task in the regulation of the innate immune system. PAMP are considered to have a novel functional role in the initiation of the innate immune receptors in animals. They have a decisive role in the revealing of microbial infection in mammals and insects. In the advancement of immunology numerous homologous genes are recognized which are given the name TLR in higher animals.

TLR Signalling

The activation of TLR is found to be associated with two different types of pathways as MyD88-dependent pathway and MyD88-independent pathway. The MyD88-dependent pathway leads to the production of inflammatory cytokines whereas MyD88-independent pathway is associated with the stimulation of IFN-β and the subsequent maturation of dendritic cells. The adaptor protein that is involved in the signalling process includes TIR-domain containing proteins, MyD88, TIRAP (TIR-associated protein), MAL (MyD88 adaptor-like protein), TRIF (TIR domain-containing adaptor protein-inducing IFN-β) and TRAM (TRIF-related adaptor molecule).

Report of TLR in Fish

The research in the case of fishes was started initially with goldfish (Carrasius auratus). The other species in which the whole genome databases are surveyed for TLR reports as Fugu fish, Zebra fish and Japanese flounder. Till date there are 10 numbers of TLR reported from human and 13 numbers of TLR reported for mice (Mus musculus) which are expressed in the number from 1 to 13. Among these the TLR-1 to TLR-9 is conserved in humans and mice. Similarly in the case of fish the conserve genes are as TLR-1 to TLR-9 as in humans. However in case of fish TLR-6 and TLR-10 does not exist.

TLR-1 and TLR-2

There are two genes commonly existing in fish and have the active role in innate modulation. A full length TLR-1 gene has been reported from the puffer fish (Tetraodon nigroviridis). They are MyD88 dependant, located in the cell surfaces. The main cell types are monocytes / macrophages, a subset of dendritic cell and B-Lymphocytes. TLR-1 and TLR-2 both can recognize gram positive bacterial cell wall components i.e. paptidoglycan (PG). This PG (lipoproteins, lipomannans and lipoteichoic acids) is the strong inducer in the case of innate immune response. In the Japanese flounder the up regulation of the TLR-1 and TLR-2 are found when stimulated with bacterial PG. This ultimately results in the higher production of cytokines as IL-6 which are involved in cellular development, inflammation function and acute phase of immune response.

TLR-3

In mammal the TLR-3 recognizes the double stranded RNA virus genome. In teleost also same report is available in case of Atlantic salmon where it resets the up regulation of Type-1 interferon (IFN). The antiviral Mx-gene is also found to be up-regulated along with IFN in the spleen and kidney. Therefore in fish TLR-3 has a great role in case of viral infection. When compared to TLR-1 and TLR-3, TLR-3 shows the TRIF dependant pathway. They are located in the cell component of dendritic cell and B-lymphocytes.

TLR-4

TLR-4 is a pattern recognition receptor able to recognize the bacterial lipopolysaccharide (LPS), results great functional role against gram negative bacteria. It is found to be associated with another molecule called MD-2 which is responsible for recognition and signaling of LPS. Only zebra fish shows the example where in other teleost the response is scanty. The production of chemokines, nitric oxide and activation of macrophage is reported in Zebrafish. The TLR-4 shows both the MyD88 dependant pathway and TRIF dependant pathways. Their locations are found to be the cell surface of peripheral macrophage / monocyte, myloid dendritic cell, mast cell, B-lymphocytes cell and intestinal epithelium.

TLR-5

TLR-5 is associated with the recognition of bacterial flagellin. They have shown the only MyD88 dependant pathway located on the cell surface of monocytes / macrophages of dendritic cells and intestinal epithelium. There are two forms of TLR5 exist as a membrane type TLR-5 (TLR-5M) and soluble type TLR-5 (TLR5S). The report is available in case of rainbow trout to recognize the flagellin of Vibrio anguillarum. The release of acute phase protein from the liver is also reported. Several other fishes show the same findings with the rainbow trout till date.

TLR-7, 8 and 9

All TLR-7, 8 and 9 are located in cell compartment and show the MyD88 dependant pathway. They can recognize the single stranded nuclic acid derived from pathogens. TLR-7 specially recognized the single stranded RNA genome of the pathogen. The cell type associated with TLR-7 is B-lymphocytes where as in case of TLR-8 mast cells are observed. Apart from these, all TLR-7, 8 and 9 are associated with monocytes / macrophages and dendritic cells. The single stranded DNA viruses were found specially to be recognized by TLR-9 only. The full length sequence of TLR-9 complementary DNA was reported in gilt head sea bream (Sparus aurata).

Novel TLRs

Though TLR-6 and TLR-10 are absent in fish, the TLR-14 is reported which termed as novel TLR. This is the special type of receptors which has the similar function as TLR-6 and 10 in case of mammal. As in fish TLR-6 and TLR-10 is absent, the TLR-14 is considered as a functional substitute for TLR-6 and TLR-10. TLR-14 recognized the multiple diacyl lipopeptide as in the mammalian in TLR-6. They are having the MyD88 dependant and a TRIF dependant pathway both. They are located on the cell surfaces of monocytes / macrophages, mast cells, and B-lymphocyte cells. Apart from these TLR-22 is also considered as a substitute for human TLR-3 in fish.

TLR v/s Therapeutics

Therapeutics evaluation of human and mouse TLR is extensively studied over the past years. It is found that they are essential receptors present in the host defence by activating the innate immune system i.e. a precondition to the initiation of adaptive immune responses. Moreover TLRs are incriminated in a wide range of inflammatory and immune disorders and take part a role in cancer treatment. There are numerous number of single nucleotide polymorphisms categorized in various TLR genes which are found to be associated with particular diseases. The application of TLR genes in different immunological tools is given in Table 1.

Table 1. Applications of TLRs in different Immunological Tools


Mouse TLRs

Human TLRs

TLR1

Flow Cytometry

Immunoprecipitation

Western Blot

TLR1

TLR2

Flow Cytometry

Western Blot

Immunohistochemistry

Functional Activity Immunoprecipitation

Immunohistochemistry (Paraffin)

Immunohistochemistry (Paraffin & Frozen)

TLR2

TLR3

Western Blot

TLR3

TLR4

Flow Cytometry

Immunoprecipitation

Functional Activity

Neutralizing

Immunohistochemistry (Paraffin & Frozen)

TLR4

TLR7

Western Blot

TLR6

TLR9


Western Blot

Flow Cytometry

Intracellular Staining/Flow Cytometry

TLR7

TLR9



Future Prospects in Fisheries

  • Functional classification is needed in case of novel TLR in teleost.

  • Experiment covering the diverse species of fishes is required.

  • The analysis by immunomoddulation of different tumour cells such as dendritic cells, monocytes and macrophages will provide valuable information regarding the vaccine development and adjuvant development.

  • As the fish leucocytes are not studied detailed till date for TLR study, there is immense scope for further research and development in this field.



References

  • Roach, J.C., Glusman, G., Rowen, L., Kaur, A., Purcell, M.K., Smith, K.D., Hood, L.E. and Aderem, A. (2005). The evolution of vertebrate Toll-like receptors. Proceedings of the National Academic Science of the United States of America, 102:9577-9582.

  • Strandskog, G., Skjaeveland, I., Ellingsen, T. and Jørgensen, J.B. (2008). Double-stranded RNA- and CpG DNA-induced immune responses in Atlantic salmon: comparison and synergies. Vaccine, 26:4704-4715.

  • Takano, T., Kondo, H., Hirono, I., Endo, M., Saito-Taki, T. and Aoki, T. (2007). Molecular cloning and characterization of Toll-like receptor 9 in Japanese flounder, Paralichthysolivaceus. Molecular Immunology, 44:1845-1853.

  • Tsujita, T., Tsukada, H., Nakao, M., Oshiumi, H., Matsumoto, M. and Seya, T. (2004). Sensing bacterial flagellin by membrane and soluble orthologs of Toll-like receptor 5 in rainbow trout (Onchorhynchus mikiss). Journal of Biological Chemistry, 279:48588-48597.

  • Verstak, B., Hertzog, P. and Mansell, A. (2007). Toll-like receptor signalling and the clinical benefits that lie within. Inflammation Research, 56:1-10.

  • http://www.invivogen.com/review-tlr

  • http://www.ebioscience.com




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