The association between CCR5, NLRC4, and AIM2 gene polymorphisms and susceptibility to tuberculosis in the Iraqi population




Abstract. Khaleel B, Al-Alwani HRS, Asmar A. 2024. The association between CCR5, NLRC4, and AIM2 gene polymorphisms and susceptibility to tuberculosis in the Iraqi population. Biodiversitas 25: 1022-1029. In immunological reactions against Mycobacterium tuberculosis, chemokines and their receptors, including CXCR3, CCR5, and RANTES, play an important role in the migration and activation of cells. The inflammasome is a multiprotein complex that serves as a master regulator of inflammation. Genetic polymorphisms contribute to individual phenotypic differences, such as disease risk and drug response. The current study was done to find the polymorphism in the CCR5, NLRC4, and AIM2 genes in our population and to look into how this polymorphism is linked to getting tuberculosis. Seventy-five tuberculosis patients participated in this study, while the control group comprised twenty-five control healthy individuals. We took two milliliters of blood from the patients and the control group and placed them in an Ethylenediaminetetraacetic acid (EDTA tube), or DNA extraction. Real-time PCR was used to find changes in the genes for CCR5 (rs2227010, rs2734648, rs1799987, rs1799988, rs1800023, rs1800024), NLRC4 (C-rs479333), and AIM2 (CC-rs1103577). Some genotypes were more common in the patient group, including SNPs CCR5 (rs2227010, rs2734648, rs1799988, rs1800023, rs1800024), NLRC4 C-rs479333, and AIM2 CC-rs1103577. However, by using Two-Two cross table the genotype of SNP CCR5-rs1799987 was not significantly different between the patient and the controls. Patients also had a lot of certain alleles for the SNPs CCR5 (rs2227010, rs1799988, rs1800023, rs1800024) and NLRC4 (rs479333). However, the alleles for the SNPs CCR5 (rs2734648, rs1799987) and AIM2 CC (rs1103577) were not very different between patients and controls. This study concludes that a polymorphism in various SNPs of the CCR5, NLRC4, and AIM2 genes may be a risk factor for tuberculosis.


Abate E, Blomgran R, Verma D, Lerm M, Fredrikson M. Polymorphisms in CARD8 and NLRP3 are associated with extrapulmonary TB and poor clinical outcome in active TB in Ethiopia. Sci Rep (2019) 9:3126. DOI: 10.1038/s41598-019-40121-8
Barletta-Naveca RH, Naveca FG, de Almeida VA, Porto JIR, da Silva GAV, Ogusku MM, et al. Toll-like receptor-1 single-nucleotide polymorphism 1805T/G is associated with a predisposition to multibacillary tuberculosis. Front Immunol (2018) 9:1455. DOI: 10.3389/fimmu.2018.01455
?Blanco, R., Gómez de Cedrón, M., Gámez-Reche, L., Martín-Leal, A., González-Martín, A., Lacalle, R. A., ... & Mañes, S. (2021). The chemokine receptor CCR5 links memory CD4+ T cell metabolism to T cell antigen receptor nanoclustering. Frontiersin Immunology, 12,722320.? DOI:10.3389/fimmu.2021.722320
Carpenter D, Taype C, Goulding J, Levin M, Eley B, Anderson S. M.-A. Shaw, and J.a.L. Armour. CCL3L1 copy number, CCR5 genotype, and susceptibility to tuberculosis. BMC Med Genet (2014) 15:5. DOI: 10.1186/1471-2350-15-5
Carpenter D, Taype C, Goulding J, Levin M, Eley B, Anderson S. M.-A. Shaw, and J.a.L. Armour. CCL3L1 copy number, CCR5 genotype, and susceptibility to tuberculosis. BMC Med Genet (2014) 15:5. DOI: 10.1186/1471-2350-15-5
Chen, L., Deng, H., Cui, H., Fang, J., Zuo, Z., Deng, J., ... & Zhao, L. (2018). Inflammatory responses and inflammation-associated diseases in organs. Oncotarget, 9(6), 7204. DOI: 10.18632/oncotarget.23208
Domingo-Gonzalez, R., Prince, O., Cooper, A., & Khader, S. A. (2016). Cytokines and chemokines in Mycobacterium tuberculosis infection. Microbiology spectrum, 4(5), 4-5.? DOI:10.1128/microbiolspec.tbtb2-0018-2016
Donadi, E. A., Mendes-Junior, C. T., Cai, H. H., Yao, Y., Zhang, S., Shi, L., ... & Shi, L. (2021). CCR5 Promoter Polymorphisms Associated With Pulmonary Tuberculosis in a Chinese Han Population. The Role of Gene Polymorphism in Modulating the Immune Responses against Tropical Infectious Diseases.? DOI: 10.3389/fimmu.2020.544548
Fernandes FP, Leal VNC, Souza de Lima D, Reis EC, Pontillo A. Inflammasome genetics and complex diseases: a comprehensive review. Eur J Hum Genet (2020) 28:13071321. DOI: 10.1038/s41431-020-0631-y
Figueira, M. B. D. A., de Lima, D. S., Boechat, A. L., Filho, M. G. D. N., Antunes, I. A., Matsuda, J. D. S., ... & Sadahiro, A. (2021). Single-nucleotide variants in the AIM2–absent in melanoma 2 gene (rs1103577) associated with protection for tuberculosis. Frontiers in Immunology, 12, 604975.? DOI: 10.3389/fimmu.2021.604975
Fisher, E., Padula, L., Podack, K., O’Neill, K., Seavey, M. M., Jayaraman, P., ... & Strbo, N. (2021). Induction of SARS-CoV-2 protein S-specific CD8+ T cells in the lungs of gp96-Ig-S vaccinated mice. Frontiers in immunology, 11, 3740.? DOI:10.1101/2020.08.24.265090
Forrellad, M. A., Blanco, F. C., Marrero Diaz de Villegas, R., Vázquez, C. L., Yaneff, A., García, E. A., ... & Bigi, F. (2020). Rv2577 of Mycobacterium tuberculosis is a virulence factor with dual phosphatase and phosphodiesterase functions. Frontiers in Microbiology, 11, 570794.? DOI:10.3389/fmicb.2020.570794
Jasinska, A. J., Pandrea, I., & Apetrei, C. (2022). CCR5 as a coreceptor for human immunodeficiency virus and simian immunodeficiency viruses: A prototypic love-hate affair. Frontiers in Immunology, 13, 835994.? DOI:10.3389/fimmu.2022.835994
Kauffman KD, Sallin MA, Sakai S, Kamenyeva O, Kabat J, Weiner D, et al. Defective positioning in granulomas but not lung-homing limits CD4 T-cell interactions with Mycobacterium tuberculosis-infected macrophages in rhesus macaques. Mucosal Immunol (2018) 11:462–73. DOI: 10.1038/ mi.2017.60
Kopitar-Jerala, N. (2017). The role of interferons in inflammation and inflammasome activation. Frontiers in immunology, 8, 873.? DOI: 10.3389/fimmu.2017.00873
Kouhpayeh, H. R., Taheri, M., Baziboroon, M., Naderi, M., Bahari, G., & Hashemi, M. (2016). CCL5 rs2107538 polymorphism increased the risk of tuberculosis in a sample of Iranian population. Prague Medical Report, 117(2), 90-97.? DOI: 10.14712/23362936.2016.9
Li C, Lu SC, Hsieh PS, Huang YH, Huang HI, Ying TH, et al. Distribution of human chemokine (C-X3-C) receptor 1 (CX3CR1) gene polymorphisms and haplotypes of the CC chemokine receptor 5 (CCR5) promoter in Chinese people, and the effects of CCR5 haplotypes on CCR5 expression. Int J Immunogenet (2005) 32:99–106. DOI: 10.1111/j.1744-313X.2005.00498.x
Liu, S., Liu, N., Wang, H., Zhang, X., Yao, Y., Zhang, S., & Shi, L. (2021). CCR5 promoter polymorphisms associated with pulmonary tuberculosis in a Chinese Han population. Frontiers in Immunology, 11, 544548.? DOI: 10.3389/fimmu.2020.544548
Ogishi, M., Yang, R., Rodriguez, R., Golec, D. P., Martin, E., Philippot, Q., ... & Boisson-Dupuis, S. (2022). Inherited human ITK deficiency impairs IFN-? immunity and underlies tuberculosis. Journal of Experimental Medicine, 220(1), e20220484. DOI: 10.4049/jimmunol.206.supp.52.10
Souza de Lima D, Ogusku MM, Sadahiro A, Pontillo A. Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis. Infect Genet Evol (2016) 41:240–4. DOI: 10.1016/j.meegid.2016.04.015
Souza De Lima, D., Bomfim, C. C., Leal, V. N., Reis, E. C., Soares, J. L., Fernandes, F. P., ... & Pontillo, A. (2020). Combining host genetics and functional analysis to depict Inflammasome contribution in tuberculosis susceptibility and outcome in endemic areas. Frontiers in Immunology, 11, 550624.? DOI: 10.3389/fimmu.2020.550624
Torres, A. C. M. G., Leite, N., Tureck, L. V., de Souza, R. L. R., Titski, A. C. K., Milano-Gai, G. E., ... & Furtado-Alle, L. (2019). Association between Toll-like receptors (TLR) and NOD-like receptor (NLR) polymorphisms and lipid and glucose metabolism. Gene, 685, 211-221. DOI: 10.1016/j.gene.2018.11.065
Yan S, Shen H, Lian Q, Jin W, Zhang R, Lin X, et al. Deficiency of the AIM2-ASC Signal Uncovers the STING-Driven Overreactive Response of Type I IFN and Reciprocal Depression of Protective IFN-? Immunity in Mycobacterial. J Immunol (2018) 200:3. DOI: 10.4049/jimmunol.1701177
Yang Y, Zhou X, Kouadir M, Shi F, Ding T, Liu C, et al. The AIM2 inflammasome is involved in macrophage activation during infection with virulent Mycobacterium bovis strain. J Infect Dis (2013) 208:11. DOI: 10.1093/indices/jit347
Zhang, Q., Sun, J., Wang, Y., He, W., Wang, L., Zheng, Y., ... & Jiang, X. (2017). Antimycobacterial and anti-inflammatory mechanisms of baicalin via induced autophagy in macrophages infected with Mycobacterium tuberculosis. Frontiers in Microbiology, 8, 2142.? DOI: 10.3389/fmicb.2017.02142
Zhou, J., Lv, J., Carlson, C., Liu, H., Wang, H., Xu, T., ... & Qian, Z. (2021). Trained immunity contributes to the prevention of Mycobacterium tuberculosis infection, a novel role of autophagy. Emerging Microbes & Infections, 10(1), 578-588. DOI: 10.1080/22221751.2021.1899771.