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Review on Study of Toll like Receptor 2 Gene and its Polymorphic Relationship with Mastitis in Cattle

U. T. Mundhe D. N. Das P. V. Jadhav Arun Pratap Singh
Vol 8(5), 19-30
DOI- http://dx.doi.org/10.5455/ijlr.20170814062631

Mastitis is defined as an inflammatory reaction of the parenchyma of the mammary glands to bacterial, chemical, thermal or mechanical injury. SCC is used as an indicator to detect mastitis in individual cow. TLR2 is a membrane protein, a receptor, which is expressed on the surface of certain cells and recognizes foreign substances and passes on appropriate signals to the cells of the immune system. Bovine TLR2 was assigned to Bos taurus (BTA) chromosome 17 using radiation hybrid mapping. Detection of molecular markers associated with mastitis resistance would be useful towards marker assisted selection (MAS) at an early age of dairy animals to reduce the economic losses. Hence purpose of this study is to review identification of SNPs in the bovine TLR2 gene and to evaluate their association with incidences of subclinical mastitis in dairy cattle.


Keywords : Mastitis Polymorphism Somatic Cell Count

Introduction

About 13 mammalian TLRs have been described (Akira et al., 2006) and 10 bovine TLRs have been mapped (McGuire et al., 2006). TLR2 recognizes other cell wall components including those found on Gram-positive bacteria (e.g. peptidoglycan, lipoteichoic acid, lipoproteins) and also LPS from Leptospira interrogans and Porphyromonas gingivalis (Eveline et al., 2007). TLR2 gene is assigned to Bos taurus (BTA) chromosome 17 using radiation hybrid mapping ((McGuire et al., 2006)). This gene spans about 13.2 kb of genomic DNA as reported by (Zhang et al., 2009) and consists of two exons and one intron. The first exon is spread over 179bp while the second one is 3333bp. Both the exons are interrupted by an intonic region of 9714bp. TLR2 is also known as CD282 (cluster of differentiation 282) and plays an important role in the immune system. Being membrane protein, TLR2 is specific receptor which is expressed on the surface of certain cells and recognizes foreign substances and passes an appropriate signal to the cells of the immune system. TLR2 is known to heterodimerize with other TLRs, broadening the range of stimuli signaling via TLR2, a property believed to extend the range of microbial molecules that TLR2 can recognize. TLR2 cooperates with TLR6 in response to diacylated mycoplasmal lipopeptide and associates with TLR1 to recognize triacylated lipopetides (Ozinsky, 2000). Furthermore, pathogen recognition by TLR2 is strongly enhanced by CD14 (Lotz et al., 2004).

TLR2 recognizes components from a variety of microorganisms. These include lipoproteins from pathogens such as Gram-negative bacteria, Mycoplasma and spirochetes (Aliprantis et al., 1999 and Lien et al., 2000) peptidoglycan and lipoteichoic acid from Gram-positive bacteria (Schwander et al., 1999) lipoarabinomannan from mycobacteria, a phenol-soluble modulin from Staphylococcus epidermidis, zymosan from fungi, glycolipids from Treponema maltophilum and porins that constitute the outer membrane of Neisseria (Underhill et al., 1999). TLR2 is the component of germline-encoded multigene family of PRR that are members of the TLR–interleukin 1 superfamily. These receptors recognize a great variety of PAMP, molecular motifs such as LPS, flagellin, and CpG DNA, shared by large groups of microorganism (viz., Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus uberis, Treponema maltophilum, mycobacteria, fungi, mycoplasma and spirochetes).

TLR2 is implicated in the recognition of bacterial cell wall components, such as lipopolysaccharide (LPS). To investigate in vivo role of TLR2, TLR2 deficient mice were generated. It was reported that TLR2 deficient mice responded to LPS to the same extent as wild-type mice. TLR2 macrophages were hyporesponsive to several Gram-positive bacterial cell walls as well as Staphylococcus aureus peptidoglycan. These results demonstrate that TLR2 recognize bacterial cell wall in vivo and TLR2 plays a major role in Gram-positive bacterial recognition (Takeuchi et al., 1999) Further (Goldammer et al. 2004) also reported that the gene was strongly expressed during mastitis caused by Staphylococcus aureus. TLR2 plays a role in mastitis caused by Streptococcus uberis (Swanson et al., 2009). Thus previous reports suggested that TLR2 play a role in the host response to intra mammary infections. Taken together, TLR2 presents an attractive candidate gene for mastitis resistance.

TLR2 Protein

The length of the predicted TLR2 proteins in all species ranged between 784 – 786 AAs (Jann et al. 2008). In all species, the protein shared common domain architecture: an extra-cellular domain containing 20 leucine rich repeats (LRR) between AA54 and AA584, a transmembrane domain at AA585– AA607 and an intracellular TIR domain at AA633–AA783. Structure of a typical TLR2 protein is given in Fig.1.  

Fig. 1: Typical TLR2 protein

In some domains of TLR2, sequence variation is high, particularly in the region between AA200 and AA310, comprising LRR 7–10. Most of the other domains are more conserved, particularly LRR 12 and LRR 13 (AA340–AA390) and the cytoplasmic domain (AA610-end).

TLR2 Protein Signaling Pathway for Stimulation of Immunity

TLR2 plays a major role in myeloid differentiation primary response gene 88 (MyD88) dependent pathway. In a study carried out by (Takeda and Akira, 2004) it is reported that MyD88 knockout mice did not show any production of inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-12, in response to any of the TLR ligands. Furthermore, activation of nuclear factor kappa light chain enhancer of activated B cells (NF)-κB and JNK (C Jun N terminal kinases) in response to the TLR2, TLR7, and TLR9 ligands are not observed in MyD88 knockout mice. This is evident of the fact that TLR2 signaling pathway is a MyD88 dependent pathway. However, in the case of TLR4 stimulation, LPS-induced activation of NF-κB and JNK is observed with delayed kinetics, even in MyD88 knockout cells, although these cells did not produce any inflammatory cytokines in response to LPS (Kawai et al., 1999). TLR2 recognizes foreign substances and passes an appropriate signal to MyD88. MyD88 possesses the Toll/ IL-1 receptor (TIR) domain in the C-terminal portion, and a death domain in the N terminal portion. MyD88 associates with the TIR domain of TLR2. Thus, MyD88 gets stimulated and recruits IL-1 receptor-associated kinase (IRAK) to TLRs through interaction of the death domains of both molecules. IRAK is activated by phosphorylation and then associates with tumor necrosis factor receptor- associated factor (TRAF)-6, leading to the activation of two distinct signaling pathways, viz. mitogen-activated protein kinase (MAPK) signaling pathway and IκB Kinase (IKK) signaling pathway finally leading to the activation of JNK and NF-Κb.

MyD88 binds to the cytoplasmic portion of TLR2 through interaction between individual TIR domains. Upon stimulation, IRAK-4, IRAK-1, and TRAF-6 are recruited to the receptor, which induces association of IRAK-1 and MyD88 via the death domains. IRAK-4 then phosphorylates IRAK-1. Phosphorylated IRAK-1, together with TRAF6, dissociates from the receptor and then TRAF6 interacts with TGF-β activated kinase (TAK)-1, Tak-1 binding protein (TAB)-1 and TAB-2. The complex of TRAF-6, TAK-1, TAB-1 and TAB-2 further forms a larger complex with Ubc13 and Uev1A, which induces the activation of TAK-1. Activated TAK-1 phosphorylates the IKK complex, consisting of IκB kinase (IKK)α, IKKβ, and NEMO/IKKγ, and MAP kinases, such as JNK, and thereby induces the activation of the transcription factors NF-κB and activator protein (AP)-1, respectively (Takeda and Akira, 2004). The transcription factor NF-κB, ultimately plays a role in formation of inflammatory cytokines i.e. TNF-α, IL-1β, IL-6 and IL-12. These all cytokines are involved in the pathogenesis of mastitis and thus TLR2 plays a major role in inflammatory response during infection.

Polymorphism in TLR2 Gene and its Association with SCC and Resistance against Mastitis:

For systemic genetic improvement through marker assisted selection, (Pant et al., 2007) constructed a selective DNA pool for two groups of animals separately demonstrating high and low estimated breeding values (EBVs) for SCS. Gene segments were amplified from this pool in PCR reactions and the amplicons sequenced to reveal polymorphisms. The study revealed absence of any polymorphism in the TLR2 gene in the Canadian Holstein population. In another study conducted by (Opsal et al., 2008) dense linkage maps comprising single nucleotide polymorphisms (SNPs) were constructed for the chromosomal regions harbouring TLR2 and TLR4 on bovine chromosome 17 and 8 respectively. A combined linkage and linkage disequilibrium methods were used to investigate possible associations between the TLR genes and mastitis susceptibility recorded in the Norwegian Red cattle population. The analysis did not detect any significant association between the chromosomal regions surrounding TLR2 and TLR4 and occurrence of mastitis in Norwegian red cattle.

A study carried out with the objective to find genetic variability at the molecular level in four genes: NOD2, TLR2, TLR4 and CXCR-2 that might be associated with susceptibility or resistance to mastitis. Studies involved 76 cows proven as mastitis positive and 25 healthy animals. DNA was isolated from milk samples and used for polymorphism identification. In this study, presence of polymorphism was revealed by PCR-RFLP for TLR2. One novel SNP, c.2577T>C was found in TLR2 gene (Porozynski 2008).

A study was undertaken in China by using 240 dairy cattle belonging to three breeds (Holstein, Simmental, and Sanhe cattle) for molecular characterization of TLR2 gene through PCR-SSCP analysis and sequencing. Three missense mutations at T385G, G398A, and G1884A were detected in the coding region that encoded extracellular domain. All animals were genotyped and allele frequencies were determined. The effects of TLR2 polymorphisms on somatic cell score (SCS) were analyzed and significant association was found between T385G and SCS. The mean SCS of genotype GG was significantly lower than those of genotype TT and TG respectively. No significant association was observed for SCS with G398A and G1884A (Zhang et al., 2009). Nucleotide sequences of bovine TLR2, TLR4 and TLR6 genes were screened by (Mariotti et al., 2009) to identify novel SNPs in 16 different bovine European cattle breeds. In total eight SNPs were identified of which three SNPs were found in TLR2 and were deposited in NCBI dbSNP. TLR2_738 was fixed in seven breeds (Highlands, Jersey, Limousine, Marchigiana, Maremmana, Simmenthal and South Devon). Significant deviations from Hardy-Weinberg equilibrium in the overall populations studied (p-value < 0.01) were observed in three SNPs at two loci: TLR2_591, TLR2_738 and TLR4_2043. These three SNPs (TLR2_591, TLR2_738 and TLR2_767) identified in TLR2 were suggested to be associated with disease resistance in cattle. The polymorphisms of the TLR2 gene using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 297 Chinese Holstein-Friesian cattle were studied by (Zhang et al., 2009). The relationship between gene polymorphism and somatic cell score (SCS) was also analysed. A polymorphic site was identified, where there was a mutation C->A at position 106 bp, which resulted in Asp being replaced by Glu. Genotypes AA, AB and BB were detected by digesting the fragment with restriction endonuclease EcoRV in the population. B allele was predominant and allele frequency A and B were estimated as 0.7845 and 0.2155, respectively. The χ2 test indicated that the polymorphic locus displayed no deviation from the Hardy-Weinberg equilibrium (P<0.05). In Chinese Holstein-Friesian cattle the SCS of BB and AB genotypes were significantly higher than AA genotypes. These AA genotypes were found to be beneficial in mastitis resistance. Hence, the study revealed that TLR2 could be a candidate gene associate with occurrence of mastitis for molecular marker-assisted selection breeding.

A study carried out in Holstein and Xinjiang Brown cattle for investigating the effect of TLR2 on subclinical mastitis Animals with highest and lowest SCS were chosen to sequence TLR2 gene and then the SNP sites were detected with PCR-RFLP. The results revealed presence of 3 SNP sites (E+189, E+631 and E+2260). E++189 site was suggested to be associated with resistance to mastitis for BB genotype. When E+2260 site was mutated and translated into termination codon, the SCC of individuals with AB genotype increased. It indicated that the mutation was harmful to mastitis resistance of cattle. The SCS in Xinjiang Brown cattle was lower than that in Holstein. Finally in this study E+189 and E+631 SNP sites were reported to affect mastitis resistance of cattle and the possible reason of the stronger resistance in Xinjiang Brown cattle was attributed to the differences in distribution between two breeds (HF and Xinjiang Brown cattle) for E+189 and E+631 sites (Jie et al., 2011).

Seven novel SNPs were reported in 5’ upstream of the TLR2 gene in six cattle breeds (26 Hereford, 30 Simmental, 156 Limousing, 46 Chinese indigenous Luxi Yellow cattle, 42 Bohai Black cattle and 225 Chinese Holstein cattle) by direct sequencing method. Four SNPs in the putative promoter region and six SNPs in TLR2 gene exon and 3’UTR were found. Haplotype analysis and linkage disequilibrium findings showed that a haplotype of two loci in the coding region may be used as a tolerance haplotype for bovine mastitis (Huang et al., 2011). Effect of TLR2 gene on subclinical mastitis in Holstein and Xinjiang Brown cattle were studied. Animals with highest and lowest SCS were chosen to sequence TLR2 gene and then the SNP sites were detected with PCR-RFLP. The results revealed presence of 3 SNP sites viz. E+189, E+631 and E+2260. Among these sites E++189 was found to be associated with resistance to mastitis for BB genotype. When E+2260 site was mutated and translated into termination codon, the SCC increased in animals with AB genotypes. It indicated that the mutation was harmful to mastitis resistance of cattle. The SCS in Xinjiang brown cattle was lower than that in Holstein. Finally in this study E+189 and E+631 SNP sites were reported to affect mastitis resistance of cattle and the possible reason of the stronger resistance in Xinjiang brown cattle was attributed to the differences in distribution between two breeds (HF and Xinjiang Brown cattle) for E+189 and E+631 sites (Bai et al., 2011). To evaluate the role of TLR2 during intramammary infections the association of SNPs and somatic cell scores in 151 Xinjiang Brown cattle and 138 Holsteins were analysed (Bai et al., 2012). The associations of genotypes or haplotypes with SCS were analyzed. These results revealed: 15 SNPs viz., E+653, E+945, E+978, E+1010, E+1250, E+1688, E+1707, E+1779, E+1782, E+1891, E+1995, E+2025, E+2055, E+2214 and E+2295 which were detected from 289 cows. It was observed that distribution of the 14 SNPs were significantly different from Xinjiang brown cattle and Holstein (P < 0.001) except for the E+945 (P > 0.05). In 11 SNPs (E+945, E+978, E+1010, E+1688, E+1707, E+1779, E+1782, E+1995, E+2025, E+2055 and E+2214), the SCS of AB genotypes were lower than AA genotypes (P < 0.05) in Xinjiang brown cattle. Haplotype analysis showed that the SCS of cattle with Hap5 was lower than that of Hap3 (P < 0.05). This suggests that Hap5 might play an important role in sub-mastitis resistance in Xinjiang brown cattle.

Sequencing of TLR2 gene in six diverse buffalo breeds of India, using primers designed from cattle database were carried out by (Tantia et al., 2012). It was found that the gene was 3590bp with 2 exons coding for 784 amino acids. Eight SNPs were reported in the gene at various positions in exon 2. Three of these eight SNPs were nonsynonymous. The gene was found to be highly conserved across all mammalian species and phylogenetic relationship revealed that the buffalo species have closeness with other ruminants’ viz. cattle, sheep and goat.

In India, work has been carried out at TANUVAS on goat TLR-2 gene. The full length gene has been cloned into retroviral vector and transfected into HEK293 cell line for further studies related to its role in disease resistance under the NAIP project “Toll like receptors in farm animals-Evolutionary lineages and application in disease resistance”. (http://www.naiptlr.com).

TLR2 gene in buffalo as a candidate gene for association study with mastitis resistance was studied by (Rana et al., 2013). PCR was standardized to amplify partial exon 2 (448 bp) of TLR2 gene using published primers  PCR-RFLP analysis of the partial exon 2 region of TLR2 gene was studied using Dra I, Eae I and Hph I restriction endonucleases which gave restriction products of 300bp, 148bp; 317bp, 131bp; and 200bp, 148bp, 100bp, respectively, in all the animal in that study. Hence role of exon 2 of TLR2 region with mastitis cannot be established.

Association between SNPs reported in the TLR2 gene of cattle and bovine mastitis were studied by (Prebavathy et al., 2015). Allele specific-PCR (AS-PCR) was developed for the detection of 6 SNPs (rs55617172, rs111026127, rs68268256, rs68268260, rs683343170 and rs68266268) which were reported to be responsible for change in amino acid present on the LRR- functional domain of TLR2 gene. Statistical analysis of association between genotype detected with the cases and control resulted in the identification of association (p= 0.0328) between TT genotype for SNP T→G at 385 mRNA position with the control and heterozygous genotype, CT for SNP C→T at 2010 mRNA position (p=0.0006) with the mastitis. Odds Ratio (OR) analysis with 95% Confidence Interval (CI) further confirmed significant (OR= 5.76, 95% CI= 2.07-15.97) association between the CT (C→T at 2010 mRNA position) heterozygous genotype and mastitis.

Organisms Causing Subclinical Mastitis

Epidemilogical analysis revealed that most of the prevalent agents associated with mastitis are Staphylococus aureus (s. Aureus), Streptococcus strains and Escherichia coli (E. coli ) pathogens (Chaneton et al., 2008). The principal organisms associated with bovine mastitis can be classified as contagious (Staphylacoccus aureus and Streptococcus agalactiae) and environmental (Streptococcus disgalactia, Streptococcus uberis and Escherichia coli) depending on their primary reservoir such as environmental versus infected mammary gland quarter (Riffon et al., 2001). The effect of different pathogens on quarter SCC was studied (Djabri et al., 2002). The average SCC for quarters infected with minor pathogens was between 1, 10,000 cells/ml and 1, 50,000 cells/ml, and that for quarters infected with major pathogens was higher than 3, 50,000 cells/ml. The highest mean value was found in mastitis caused by coliforms and Streptococcus uberis (over 1 million cells/ml). Further, (Carrillo-Casas et al., 2012) reported that SCC values of 1, 00,000 to 7, 00,000 cells/ml are associated with the presence of Staphylococcus aureus and Streptococcus spp. The environmental pathogens are accountable for most mastitis episodes on well managed farms too and majority of cases of IMI caused by environmental pathogens are attributed to coliforms and environmental streptococci (Guterbock ,1992 and Radostits et al., 2000). Further investigation carried out by (Bradley 2002) the commonest cause responsible for 40.9% of all mastitis cases were enterobacteriacae. Occurrence of mastitis due to coliform bacteria has been reported worldwide (Shipigel, 2001). This includes mostly the organisms of Enterobacteriaceae family (viz. E. coli, Klebsiella spp. and Enterobacter spp. etc). The environmental and contagious pathogens are accountable for approximately 90 per cent economically important mastitis (Soback, 1990).

SSC as an indication of mastitis, suggested that the cell count more than 5,00,000 cells/ml to be considered as the positive indication of mastitis (Narayan and Iya 1954, Sheldrake and Hoare 1981 and Jha et al., 1993). The original limit for SCC of a healthy quarter indicated by the (IDF 1971) is 5,00,000 cells/ml. Recently (Sharma et al., 2008 and 2010) interpreted that the animals classified into subclinical category if no gross abnormalities are present in milk or udder but there is growth of bacteria on culture media and the threshold level of SCC would be 2,00,000 cells/ml of milk.

On the contrary, from the research conducted by (Das et al. 2008) to detect latent and sub clinical mastitis in cows and buffalo from different organized herds in Kolkata, it was inferred that a SCC value of 7, 00,000 cells/ml of milk would be the cut off value for detection of subclinical mastitis.

Table1: SCC values of milk in animals affected by subclinical mastitis

Breed/Species SCC                              (*105 cells/ml) References
Karan Freies 8.3 ± 0.69 (Samanta et al., 2006)
Karan Swiss 7.2 ± 0.7

11.28 ± 0.92

(Samanta et al., 2006)

(De and Mukherjee, 2009)

HF x Brown Swiss x Hariyana 10.54 ± 0.7 (De and Mukherjee, 2009)
HF x Jersey x Hariyana 10.8 ± 1.14 (De and Mukherjee, 2009)
Brown Swiss x HF x Hariyana 11.19 ± 1.5 (De and Mukherjee, 2009)
HF x Hariyana 15.51 ± 0.94 (De and Mukherjee, 2009)
Crossbreds 2.7 – 2.98 (Elango et al., 2010)
Crossbreds 3.58 – 4.04 (Singh and  Garg,  2011 and 2012)
Crossbreds 2.34 ± 0.44 Gera  and Guha (2012)
Crossbreds 1.22 (Tarate et al., 2012)
Vrindavani cattle 5.07 ± 0.17 (Gupta et al., 2016)
Jersey crossbreds 7.60 ± 0.25 (Mundhe et al., 2016)
Deoni cattle 3.4 ± 0.03 (Mundhe et al., 2016)
HF Crossbreds 5.2 ± 0.05 (Jadhav, 2014)
Jersey crossbreds 10.2 ± 0.06 (Mundhe et al., 2015)
Deoni cattle 2.4 ± 0.05 (Mundhe et al., 2016)

Conclusion

Significant role of dairy sector towards national economy has been achieved through enhancement of milk production of the country by crossbred dairy animals and indigenous milch and dual purpose animals. It is well established that dairy animals which are superior in milk production are usually highly susceptible to disease like mastitis. Somatic cell count indicates health status of an udder as well as of animal. Selection of animals having low incidence of mastitis or better tolerance against intra mammary infection is a choice of breeder as well as farmers. The range of mean somatic cell count varies from 2.4 ± 0.05 lakhs in indigenous to 7.6 ± 0.25 lakhs in crossbred dairy cattle under Indian conditions. SNPs of TLR2, disease tolerance gene and their significant association with udder health including occurrence of subclinical and clinical mastitis provides an indication for selection of animals through marker information at an early age. Hence, based on genotype information, genetic or genomic selection will probably be one of the most important options for estimating true breeding value for selection of superior dairy animals in future.

Competing Interests

The author declares that they have no competing interests.

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