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SLC11A1 genetic variation and low expression may cause immune response impairment in TB patients

Genes & Immunity volume 23, pages 85–92 (2022)Cite this article

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Abstract

Tuberculosis (TB) is caused by Mycobacterium tuberculosis. Host genetic factors are important for the detection of TB susceptibility. SLC11A1 is located in monocyte phagolysosomes that help to limit M. tuberculosis growth by transferring divalent cations across the membrane. Genetic variation in SLC11A1 may alter its expression and increase the susceptibility of individuals to TB. The current study aimed to provide insight into host genetic variations and gene expression in TB patients. A total of 164 TB patients and 85 healthy controls were enrolled in this study. SLC11A1 polymorphisms were detected by PCR-RFLP. Real-time qPCR was used for SLC11A1 gene expression, and ELISA was used for protein estimation. GTEx Portal was used for quantitative trait loci analysis, while the STRING (v.11) web platform was used for gene interactive network construction. Data were analyzed using SPSS, GraphPad Prism, Haploview, and SNPstats. SLC11A1 polymorphisms and combinatorial genotypes were strongly associated with TB susceptibility, which may explain the greater prevalence of tuberculosis in the local population. Polymorphisms in SLC11A1 have also been linked to gene expression variation. Furthermore, the expression of SLC11A1 was downregulated in TB patients, which may influence the function of other associated genes and may impair the immunological response to tuberculosis.

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Fig. 1: SLC11A1 PCR-RFLP analysis for polymorphism.
Fig. 2: SLC11A1 linkage disequilibrium, quantitative trait loci, and gene interaction network analysis.
Fig. 3: SLC11A1 gene expression and serum level in TB patients and healthy controls.

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References

  1. Ottenhoff THM, Kaufmann SHE. Vaccines against tuberculosis: where are we and where do we need to go? PLoS Pathog. 2012;8:e1002607. https://doi.org/10.1371/journal.ppat.1002607.

  2. Matlow A, Robb M, Goldman C. Infection control and paediatric tuberculosis: a practical guide for the practicing paediatrician. Paediatr Child Health (Oxf). 2003;8:624–6.

    Article  Google Scholar 

  3. Shahzad F, Bashir N, Ali A, Jabeen S, Kashif M, Javaid K, et al. Decreased classical monocytes and CD163 expression in TB patients: an indicator of drug resistance. Braz J Microbiol. 2021;52:607–17.

    Article  CAS  Google Scholar 

  4. Lee J, Boyce S, Powers J, Baer C, Sassetti CM, Behar SM. CD11cHi monocyte-derived macrophages are a major cellular compartment infected by Mycobacterium tuberculosis. PLoS Pathog. 2020;16:1–30.

    Article  CAS  Google Scholar 

  5. Cohen SB, Gern BH, Delahaye JL, Adams KN, Plumlee CR, Winkler JK, et al. Alveolar macrophages provide an early mycobacterium tuberculosis niche and initiate dissemination. Cell Host Microbe. 2018;24:439.e4

    Article  Google Scholar 

  6. Murray MF. Susceptibility and response to infection [Internet]. Emery and Rimoin’s Principles and Practice of Medical Genetics. Elsevier Ltd; 2013. 1–24. Available from: https://doi.org/10.1016/B978-0-12-383834-6.00047-1.

  7. Li X, Yang Y, Zhou F, Zhang Y, Lu H, Jin Q, et al. SLC11A1 (NRAMP1) polymorphisms and tuberculosis susceptibility: Updated systematic review and meta-analysis. PLoS ONE. 2011;6:2–9.

    Google Scholar 

  8. Caws M, Thwaites G, Dunstan S, Hawn TR, Lan NTN, Thuong NTT, et al. The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS Pathog. 2008;4:e1000034.

  9. Casanova JL, Abel L. Genetic dissection of immunity to mycobacteria: the human model. Annu Rev Immunol. 2002;20:581–620.

    Article  CAS  Google Scholar 

  10. Bidwell J, Keen L, Gallagher G, Kimberly R, Huizinga T, McDermott MF, et al. Cytokine gene polymorphism in human disease: On-line databases, Supplement 1. Genes Immun. 2001;2:61–70.

    Article  CAS  Google Scholar 

  11. Cai L, Li Z, Guan X, Cai K, Wang L, Liu J, et al. The research progress of host genes and tuberculosis susceptibility. Oxid Med Cell Longev. 2019;2019:8. https://doi.org/10.1155/2019/9273056.

  12. Liu W, Cao WC, Zhang CY, Tian L, Wu XM, Habbema JDF, et al. VDR and NRAMP1 gene polymorphisms in susceptibility to pulmonary tuberculosis among the Chinese Han population: a case-control study. Int J Tuberc Lung Dis. 2004;8:428–34.

    CAS  PubMed  Google Scholar 

  13. Bellamy R. Susceptibility to mycobacterial infections: the importance of host genetics. Genes Immun. 2003;4:4–11.

    Article  CAS  Google Scholar 

  14. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.

    Article  CAS  Google Scholar 

  15. Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, et al. The genotype-tissue expression (GTEx) project. Nat Genet. 2013;45:580–5.

    Article  CAS  Google Scholar 

  16. Søborg C, Andersen AB, Madsen HO, Kok-Jensen A, Skinhøj P, Garred P. Natural resistance-associated macrophage protein 1 polymorphisms are associated with microscopy-positive tuberculosis. J Infect Dis. 2002;186:517–21.

    Article  Google Scholar 

  17. Hsu YH, Chen CW, Sun HS, Jou R, Lee JJ, Su IJ. Association of NRAMP 1 gene polymorphism with susceptibility to tuberculosis in Taiwanese aboriginals. J Formos Med Assoc. 2006;105:363–9.

    Article  CAS  Google Scholar 

  18. Velez DR, Hulme WF, Myers JL, Stryjewski ME, Abbate E, Estevan R, et al. Association of SLC11A1 with tuberculosis and interactions with NOS2A and TLR2 in African-Americans and Caucasians. Int J Tuberc Lung Dis. 2009;13:1068–76.

    CAS  PubMed  Google Scholar 

  19. Ryu S, Park YK, Bai GH, Kim SJ, Park SN, Kang S. 3’UTR polymorphisms in the NRAMP1 gene are associated with susceptibility to tuberculosis in Koreans. Int J Tuberc Lung Dis. 2000;4:577–80.

    CAS  PubMed  Google Scholar 

  20. Kim JH, Lee SY, Lee SH, Sin C, Shim JJ, In KH, et al. NRAMP1 genetic polymorphisms as a risk factor of tuberculous pleurisy. Int J Tuberc Lung Dis. 2003;7:370–5.

    CAS  PubMed  Google Scholar 

  21. Harishankar M, Selvaraj P, Bethunaickan R. Influence of genetic polymorphism towards pulmonary tuberculosis susceptibility. Front Med. 2018;5:1–1.

    Article  Google Scholar 

  22. Chen Xrong, Feng Ylin, Ma Y, Zhang Zde, Li Cyou, Wen Fqiang, et al. A study on the haplotype of the solute carrier family 11 member 1 gene in Tibetan patients with pulmonary tuberculosis in China. Zhonghua Jie He He Hu Xi Za Zhi. 2009;32:360–4.

    PubMed  Google Scholar 

  23. Shastry BS. Single nucleotide polymorphisms: impact on gene function & phenotype. Single Nucleotide Polymorph Methods Protoc. 2009;578:1–22.

    Google Scholar 

  24. Zaahl MG, Robson KJH, Warnich L, Kotze MJ. Expression of the SLC11A1 (NRAMP1) 5′-(GT)n repeat: opposite effect in the presence of −237C→T. Blood Cells, Mol Dis. 2004;33:45–50.

    Article  CAS  Google Scholar 

  25. Gazouli M, Atsaves V, Mantzaris G, Economou M, Nasioulas G, Evangelou K, et al. Role of functional polymorphisms of NRAMP1 gene for the development of Crohn’s disease. Inflamm Bowel Dis. 2008;14:1323–30.

    Article  Google Scholar 

  26. Searle S, Blackwell JM. Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility. J Med Genet. 1999;36:295–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wiredja D, Bebek G. Identifying gene interaction networks. Methods Mol Biol. 2017;1666:539–56.

    Article  CAS  Google Scholar 

  28. Lewis Marffy AL, McCarthy AJ, et al. Leukocyte Immunoglobulin-Like Receptors (LILRs) on human neutrophils: modulators of infection and immunity. Front Immunol. 2020;11:857 https://doi.org/10.3389/fimmu.2020.00857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Duhan V, Hamdan TA, Xu HC, Shinde P, Bhat H, Li F, et al. NK cell–intrinsic FcεRiγ limits CD8+ T-cell expansion and thereby turns an acute into a chronic viral infection. PLoS Pathog. 2019;15:1–20.

    Article  Google Scholar 

  30. Feng Y, Cohen SN. Upregulation of the host slc11a1 gene by clostridium difficile toxin b facilitates glucosylation of rho gtpases and enhances toxin lethality. Infect Immun. 2013;81:2724–32.

    Article  CAS  Google Scholar 

  31. Cellier MFM. Cell-type specific determinants of NRAMP1 expression in professional phagocytes. Biol (Basel). 2013;2:233–83. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4009858&tool=pmcentrez&rendertype=abstract.

  32. Govoni G, Gauthier S, Billia F, Iscove NN, Gros P. Cell-specific and inducible Nramp1 gene expression in mouse macrophages in vitro and in vivo. J Leukoc Biol. 1997;62:277–86.

    Article  CAS  Google Scholar 

  33. Stober CB, Brode S, White JK, Popoff J-F, Blackwell JM. Slc11a1, formerly Nramp1, is expressed in dendritic cells and influences major histocompatibility complex class II expression and antigen-presenting cell function. Infect Immun. 2007;75:5059–67.

    Article  CAS  Google Scholar 

  34. Sullivan KM, Dean A, Minn MS. OpenEpi: a web-based epidemiologic and statistical calculator for public health. Public Health Rep. 2009;124:471–4.

    Article  Google Scholar 

  35. Asai S, Abe Y, Fujino T, Masukawa A, Arami S, Furuya H, et al. Association of the SLC11A1 gene polymorphisms with susceptibility to mycobacterium infections in a japanese population. Infect Dis Clin Pract. 2008;16:230–4.

    Article  Google Scholar 

  36. Barker K. Phenol-Chloroform Isoamyl Alcohol (PCI) DNA Extraction. In: Barker K, Tett S (eds). At the bench: a laboratory navigator. 1st edn. (Cold Spring Harbor Laboratory Press, New York, 1998) pp 284–289.

  37. Niño-Moreno P, Turrubiartes-Martinez E, Oceguera-Maldonado B, Baltazar-Benítez N, Negrete-González C, Oliva-Ramírez B, et al. The role of NRAMP1/SLC11A1 gene variant D543N (1730G/A) in the genetic susceptibility to develop Rheumatoid arthritis in the Mexican Mestizo population. Rev Investig Clin. 2017;69:5–10.

    Google Scholar 

  38. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25:402–8.

    Article  CAS  Google Scholar 

  39. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: Protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:D447–52.

    Article  CAS  Google Scholar 

  40. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22:1928–9.

    Article  Google Scholar 

  41. Varzari A, Deyneko IV, Tudor E, Grallert H, Illig T. Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in a Moldavian population. Innate Immun. 2021;27:365–76.

    Article  CAS  Google Scholar 

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Acknowledgements

We sincerely acknowledge the University of Health Sciences Lahore for supporting this study.

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Authors and Affiliations

  1. Department of Immunology, University of Health Sciences, Lahore, Pakistan

    Faheem Shahzad, Atia Ali, Ali Ammar, Mohammad Kashif, Khursheed Javaid, Shah Jahan, Romeeza Tahir & Nadeem Afzal

  2. Department of Livestock Management, Agriculture University Faisalabad, Faisalabad, Pakistan

    Noman Bashir

  3. Continental Medical College, Lahore, Pakistan

    Ayesha Nadeem

  4. Ameer-Ud-Din Medical College, Lahore, Pakistan

    Muhammad Rizwan

  5. Services Institute of Medical Sciences, Lahore, Pakistan

    Abid Mushtaq

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  1. Faheem Shahzad
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Contributions

FS contributed by conceiving, planning, and designing the work, acquiring, analyzing, and interpreting the data, writing and submitting the work. NB contributed by acquiring, drafting, and revising the work. AtA and AN contributed by acquiring, analyzing, and interpreting the data. AAm contributed by analyzing and interpreting the data and revising the work. MK contributed by acquiring the data and by revising the work. KJ contributed by acquiring the data and by revising the work. SJ contributed by conceiving and designing the work, by analyzing and interpreting the data and supervising the work. RT contributed by designing, drafting and revising the work. MR contributed by designing the work and analyzing the data. AM contributed by acquiring and analyzing the data. NA contributed by conceiving and designing the work, by analyzing and interpreting the data, revising and approving the final draft and supervising the overall work.

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Correspondence to Faheem Shahzad.

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Shahzad, F., Bashir, N., Ali, A. et al. SLC11A1 genetic variation and low expression may cause immune response impairment in TB patients. Genes Immun 23, 85–92 (2022). https://doi.org/10.1038/s41435-022-00165-9

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