Abstract
Mycobacterium tuberculosis (MTB) is the causative agent of pulmonary tuberculosis (PTB), a major health problem that leads to 1.5 million deaths annually. Host genetic factors play a significant role in disease resistance/susceptibility by altering immunity against MTB. Toll-like receptor (TLR) sensors such as TLR2, TLR4, TLR8, and TLR9 are known to play a pivotal role in PTB via modulating sensor expression and/or effector responses. Single-nucleotide polymorphism (SNP) rs187084 (T-1486C) of the TLR9 promoter is associated with various autoimmune disorders and cancers. A recent bioinformatic analysis predicted that the T-1486C SNP is involved in PTB, although its potential role is unclear. To investigate the role of T-1486C in PTB, we stimulated PBMCs with the H37Rv whole cell lysate. We found that the presence of the “C” allele increases the transcriptional activity of the TLR9, which in turn induces high levels of Interferon gamma-induced protein 10 (IP-10), a biomarker for PTB. However, the expression of protective cytokines such as IFNγ and TNFα was observed significantly less with “C” allele in comparison to “T” allele. We further selected three different tribe populations showing differential susceptibility to PTB and performed genotypic analyses for the TLR9 promoter. We found a significantly lower minor allele frequency (MAF) of T-1486C in the Baiga tribe, wherein fewer PTB cases were reported, than that in the Gond and Korku tribes. Collectively, these data suggest that the minor “C” allele at rs187084 locus may be associated with susceptibility to PTB, which may explain the relatively lower PTB rates observed in Baiga tribe members.
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Acknowledgments
Authors would like to thank the sequencing facility of Department of Biological Sciences, IISER Bhopal. D.B. would like to thank for PDF support from IISER Bhopal. We would also like to thank Raunaq Singh Nagi for reading our manuscript and for helpful suggestions. This work is supported by research grants number SR/S2/RJN-55/2009 and BT/PR6009/GBD/27/382/2012 from Department of Science and technology (DST) and Department of Biotechnology (DBT), Government of India (H.K.); MPCST3657/CST/BTA (D.B.) and Intramural Research Grant of IISER, Bhopal, India.
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Deepak Bharti, Ashish Kumar, and Ranjeet Singh Mahla contributed equally to this work.
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Fig S1
For analysis of percentage population of TLR9 positive PBMCs, cells were excluded from background noise and cellular debris. The FITC fluorescence was measured in log scale. This is one of the representative experiments for individuals with TT (fig A) and TC (fig B) genotype, showing differential expression of TLR9 receptor as percentage positive cells. (PDF 258 kb)
Table S1
Genotype and allele frequency was calculated for the rs187084 and rs5743836 in the central India tribes. Chi- Square value was calculated by observed and expected genotype frequency. (PDF 15 kb)
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Bharti, D., Kumar, A., Mahla, R.S. et al. The role of TLR9 polymorphism in susceptibility to pulmonary tuberculosis. Immunogenetics 66, 675–681 (2014). https://doi.org/10.1007/s00251-014-0806-1
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DOI: https://doi.org/10.1007/s00251-014-0806-1