Lara Ghali A.Ali, Nawal Mohammed Utba, Ahmed Asmer Mankhi




The innate immune system has evolved as the first line of defense against microorganisms, which involves specific pathogen recognition receptors such as toll-like receptors (TLR). The aim of the present study was to investigate whether the TLR2 gene polymorphism could influence the susceptibility to pulmonary tuberculosis (TB) and its expression level as well as its concentration in patients’ sera.


A total of 120 subjects, including 80 patients with TB including 40 multiple drug resistance (MDR), 20 recently diagnosed (RD) and 20 old cases (OC) of TB patients, in addition to 40 healthy control, were examined for TLR2 polymorphism over locus -100 microsatellite guanine-thymine repeats, 24969 (T>C) and 5305 (C>T). TLR2 gene expression was assayed using a real time PCR technique; furthermore, sera from 68 TB patients and 20 healthy control were assayed for TLR2 level using ELISA technique.


We found that the TC genotypes showed a significantly increased frequency in MDR patients than control (35% vs.12.5%, respectively; **P = 0.034), and the associated OR value 3.77 with EF value of 0.25. That may regard TLR-2 rs3804100 TC as TB susceptibility genotype in the investigated Iraqi patients. Whereas the TLR-2 serum levels varied significantly (*p<0.05) between studied groups in regard to TT genotypes. For TLR-2 rs7696323, all TB patients and control groups have CC genotypes (Wild type). In respect to (GT)n microsatellite repeat; GT repeat alleles had insignificant differences (p > 0.05) between MDR and OC than control groups, while RD group was significantly higher [**P = 0.006] than control group in GT(24) repeat allele, with OR value of 5.2 and EF value of 0.33. Furthermore, this GT repeat allele associated with susceptibility to TB. For TLR-2 gene expression, the results revealed a significant decrease (*p< 0.05) in TB patients in comparison to control groups. A novel TLR-2 rs3804100 SNPs were detected in Iraqi Arabs at g.24870 in 15%, g.24864 in 1.25% and g.25212 in 32.5% of patients. Nevertheless, in control the novel SNPs were g.24887 in 2.5%, g.25212 in 7.5% and g. 25216 in 7.5%. On the other hand, a novel TLR-2 rs7696323 SNPs were determined in Iraq Arabs patients and control at g.23934 in 10%, g.23564 in 1.25%, g.23460 in 6.25%, g.23445 in 11.25%, g. 23452 in 10% and g. 23477 in 10% of TB patients. While in control group, g.23957 in 7.5%, g.23438 in 7.5%, g.23445 in 7.5%, g.23452 in 32.5% and g.23443 in 2.5% of control.


TLR2 genetic polymorphisms influence susceptibility to pulmonary TB. TLR2 variants play a role in the development of TB disease, probably by affecting TLR2 expression level. Moreover, the present study showed that during anti-tuberculosis treatment, which were seems likely responsible for controlling infection and excess inflammation

Full Text:



Issa AH and Salman MS. Polymorphism of interferon gamma promoter and receptor among tuberculosis patients in Basra province, south of Iraq. Dannish journal of medicine and medical sciences 2017; 4(1):1-7.

WHO. Global tuberculosis report. World health organization: Geneva.2013.

WHO. "Totally Drug-Resistant TB: a WHO consultation on the diagnostic definition and treatment options" (PDF). Who.int. World Health Organization. Retrieved 25 March 2016.

Wilkinson RJ. Human genetic susceptibility to tuberculosis: time for a bottom-up approach? J Infect Dis 2012; 205: 525-7.

Bhatt K, Salgame P. Host innate immune re¬sponse to Mycobacterium tuberculosis. J Clin Immunol 2007; 27: 347-62.

Cao B, White JM, Williams SJ. Synthesis of gly¬coconjugate fragments of mycobacterial phos¬phatidylinositol mannosides and lipomannan. Beilstein J Org Chem 2011; 7: 369-77.

Chen YC, Hsiao CC, Chen CJ, Chin CH, Liu SF, Wu CC, et al. Toll-like receptor 2 gene polymor¬phisms, pulmonary tuberculosis, and natural killer cell counts. BMC Med Genet 2010; 11: 17.

Drennan MB, Nicolle D, Quesniaux VJ, Jacobs M, Allie N, Mpagi J, et al. Toll-like receptor 2-defi¬cient mice succumb to Mycobacterium tuber¬culosis infection. Am J Pathol 2004; 164: 49-57.

Saraav I, Singh S, Sharma S. Outcome of Mycobacterium tuberculosis and Toll-like re-ceptor interaction: immune response or im¬mune evasion? Immunol Cell Biol 2014; 92: 741-6.

Taxereau J, Chiche JD, Taylor W, Choukroun G, Comba B, Mira JP. The importance of toll-like receptor 2 polymorphisms in severe infections. Clin Infect Dis 2005; 41(Suppl 7):S408-15.

Haehnel V, Schwarzfischer L, Fenton MJ, Rehli M. Transcriptional regulation of the human toll-like receptor 2 gene in monocytes and macrophages. J Immunol 2002;168(11):5629-5637.

Yim JJ, Lee HW, Lee HS, Kim YW, Han SK, Shim YS, et al. The association between microsatellite polymorphisms in intron II of the human toll-like receptor 2 gene and tuberculosis among Koreans. Genes Immun 2006; 7(2):150-155.

Wu, Yi Hu, Dange Li, Weili Jiang, Biao Xu. Screening toll-like receptor markers to predict latent tuberculosis infection and subsequent tuberculosis disease in a Chinese population. Linlin BMC Medical Genetics 2015; 1: 16:19

Thuong NT, Hawn TR, Thwaites GE, Chau TT, Lan NT, Quy HT, et al. A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun 2007; 8(5):422-428.

Prabha C, Rajashree P, Sulochana DD. TLR2 and TLR4 expression on the immune cells of tuberculous pleural fluid. Immunol Lett 2008; 117(1):26-34.

Sutmuller RPM, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ, et al. Toll-like receptor 2controls expansion and function of regulatory T cells. J Clin Invest 2006; 116(2):485-494.

Al-Bakry G. principles of genetic engineering. University of Basra, College of Sciences. 1991.

Yuan HY, Chiou JJ, Tseng WH, Liu CH, Liu CK, Lin YJ, et al. FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization. Nucleic Acids Res. 2006; 1(34) Web Server: w635-w641.

Ogus AC, Yoldas B, Ozdemir T, Uguz A, Olcen S, Keser I, et al. The Arg753GLn poly¬morphism of the human toll-like receptor 2 gene in tuber¬culosis disease. Eur Respir J. 2004; 23: 219-223.

Yim JJ, Ding L, Schäffer AA, Park GY, Shim YS, Holland SM. A microsatellite polymorphism in intron 2 of human toll-like receptor 2 gene: functional implications and racial differences. FEMS Immunol Med Microbiol 2004; 40(2):163-169.

Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, de Beaucoudrey L, Feinberg J, et al. Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin Immunol 2006; 18(6): 347-361

Reiling N, Holscher C, Fehrenbach A, Kroger S, Kirschning CJ, Goyert S, et al. Cutting edge: Toll-like receptor [TLR]2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J Immunol 2002; 169:3480–3484.

Ma X, Liu Y, Gowen BB, Graviss EA, Clark AG, Musser J. Full-Exon Resequencing Reveals Toll-Like Receptor Variants Contribute to Human Susceptibility to Tuberculosis Disease PLoS ONE 2007; 2(12): e1318.

Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, et al. Synonymous mutations in the human dopamine receptor D2 [DRD2] affect mRNA stability and synthesis of the receptor. Hum Mol Genet 2003; 12:205–16.

Xue Y, Jin L, Li A, Wang H, Li M, Zhang Y, et al. Microsatellite polymorphisms in intron 2 of the toll-like receptor 2 gene and their association with susceptibility to pulmonary tuberculosis in Han Chinese. Clin Chem Lab Med. 2010; 48(6):785–789.

Fang X, Lan-pin X, Ya-kun D, Hui Q, Lin S, Jie-qiong L, et al. Association between Polymorphisms of Toll like receptor 2 and the suseptibility to tuberculosis in Chinese Han children. Chinese Journal of Evidence -Based Pediatric. 2014; 9(6): 441-446

Suryadevara NC, Neela VS, Devalraju KP, Jain S. SivaSai KS, Valluri VL, et al. Influence of Intron II microsatellite polymorphism in human toll-like receptor 2 gene in leprosy. Hum Immunol. 2013; 74:1034±1040.

Salie M, Daya M, Lucas LA, Warren RM, Van der Spuy GD, van Helden PD, et al. Association of toll-like receptors with susceptibility to tuberculosis suggests sex-specific effects of TLR8 polymorphisms. Infect Genet Evol. 2015; 34: 221±229.

Veltkamp M, Wijnen PAHM, van Moorsel CHM, Rijkers GT, Ruven HJT, Heron M. et al. Linkage between Toll-like [TLR] 2 promotor and intron polymorphisms: functional effects and relevance to sarcoidosis. Clin Exp Immunol. 2007; 149:453–62.

Newport MJ, Allen A, Awomoyi AA, Dunstan SJ, McKinney E, Marchant A, et al. The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia. Tuberculosis (Edinb). 2004 84(6):347–52.

Schroder NW and Schumann RR. Single nucleotide polymorphisms of toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis. 2005; 5 (3):156–64.

Chang JS, Huggett JF, Dheda K, Kim LU, Zumla A, Rook GA. Mycobacterium tuberculosis induces selective up-regulation of TLRs in the mononuclear leukocytes of patients with active pulmonary tuberculosis. J Immunol 2006; 176:3010–8.

Pennini ME, Pai RK, Schultz DC, Boom WH, Harding CV. Mycobacterium tuberculosis 19-kda lipoprotein inhibits IFN-gamma-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling. J Immunol 2006; 176(5):4323–30.

Larionov A, Krause A, Miller WR. A standard curve based method for relative real time PCR data processing. BMC Bioinformatics. 2005; 21: 6–62.

Oliveira LRCd, Peresi E, Golim MdA, Gatto M, Arau´ jo Junior JP et al. Analysis of Toll-Like Receptors, iNOS and Cytokine Profiles in Patients with Pulmonary Tuberculosis during Anti-Tuberculosis Treatment. PLoS ONE. 2014; 9(2): e88572.

Quesniaux VC, Fremond M, Jacobs S, Parida D, Nicolle V, Yeremeev F, et al. Toll-like receptor pathways in the immune responses to mycobacteria. Microbes Infect. 2004; 6:946–959.

Kim AZ, Graham AW, Rook JC, Jim F, Huggett KD, Louise U. Pulmonary Tuberculosis Leukocytes of Patients with Active Up-Regulation of TLRs in the Mononuclear Myobacterium tuberculosis Induces Selective J Immunol 2006; 176:3010-3018.

Ad'hiah, A. H. Immunogenetic studies in selected human diseases. Ph. D. dissertation, department of human genetic, University of Newcastle upon Tyne, England. 1990.


  • There are currently no refbacks.