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TOLL-LIKE RECEPTORS IN FARM ANIMALS - EVOLUTIONARY
LINEAGES AND APPLICATION IN DISEASE RESISTANCE
     
Whenever a pathogen invades a host, the host mounts an innate immune response primarily to keep the pathogen under check before the specific immunity consisting of antibodies and immune cells fights the pathogen more precisely. One of the components of this innate immune system is the toll-like receptors (TLRs). They recognize conserved components among various classes of pathogens / chemicals / molecules. TLRs are capable of identifying different classes of pathogen-specific structures. For example, TLR 4 recognizes lipopolysaccharide moieties in Gram negative bacteria. This recognition in turn stimulates a sequence of signaling mechanisms resulting in the production of various protein effector molecules (cytokines). These molecules serve as a link between innate and specific immune mechanisms. Thus TLRs (immune cell origin) or their specific ligands usually of pathogen-origin, can be exploited to modulate the immune response culminating in a more beneficial outcome to the host.

Bacterial cell-surface lipopolysaccharides (LPS), lipoproteins, lipopeptides and lipoarabinomannan; proteins such as flagellin from bacterial flagella, double-stranded RNA of viruses or the unmethylated CpG islands of bacterial and viral DNA, and certain other RNA and DNA are PAMPs specifically recognized by different types of TLRs.

Immune mechanisms involving immunogenic proteins of pathogens are well characterized. Another set of pathogen-derived molecules, PAMPs, that are not immunogenic and binds to TLRs, offer themselves as novel targets for immune modulation either by using TLR ligands for increasing the potency of existing vaccines or TLRs themselves as therapeutic targets.

India has a large genetic diversity with respect to buffalo and goat and hence the onus is on India to characteize this genetic diversity in terms of immune molecules such as TLR genes. There is paucity of information on the sequences, expression profiles, ligand specificity and their induced cytokine profiles in different breeds of buffalo and goat.

The role of TLRs genes in disease resistance would be elucidated using naturally occuring resistance models. In these models proposed, the target animal chosen is either susceptible to a disease or vice versa (For example, goat is susceptible to a viral disease - PPRV but resistant to a bacterial disease - Haemorrhagic septicaemia (HS) caused by Pasteurella multocida, while the reverse is true for buffalo). Use of such models would precisely highlight the role of TLRs in conferring resistance at species level.

Expression levels of TLR mRNAs in specific organs may be related to a pathogen’s ability to replicate in that organ. This hypothetic relationship has never been explored before at species level. For example, buffalo lung can facilitate better replication of Pasteurella multocida probably because of lowered expression levels of TLR 4, that is the target for LPS ligand present in the causative bacteria. If this is true, the existing HS vaccines can be potentiated using TLR 4 ligands.

Identification of novel SNPs in TLR genes related to increased basal expression levels of TLR mRNAs can be exploited in marker-assisted selection for increased disease resistance characteristics.

Yak (Bos grunniens) and Mithun (Bos frontalis) belong to the Bos family, but very little is known about their evolutionay lineages especially with respect to their immune molecules such as toll-like receptors. No information is available on the presence of TLRs and their sequence characteristics in them. Once this information is generated, more understanding would be obtained about the evolutionary relationships of these animals with bovine.

Using the sequences for buffalo and goat TLR and cytokine genes, a disease resistance DNA chip would be evolved, which is a microarray based method to quantify TLR mRNA expression for screening of buffalo and goat for disease resistance. Under this proposed project, genetic characterization of the TLRs and their expression levels in different tissues would give insight into the disease resistance characteristics of Indian breeds of buffalo and goat.



Estimated cost: Rs. 308.483 lakhs
Duration: 2008 to 2012
Department of Animal Biotechnology,
Madras Veterinary College,
Tamil Nadu Veterinary and Animal Sciences University,
Chennai - 600 007, Tamil Nadu