Allelic-Specific Regulation of xCT Expression Increases Susceptibility to Tuberculosis by Modulating microRNA-mRNA Interactions

ABSTRACT xCT forms part of the xc− cysteine-glutamate antiporter which inhibits antimicrobial inflammatory immune functions and thus increases susceptibility to tuberculosis (TB). However, the associations between xCT gene polymorphisms and susceptibility to TB, as well as whether these modulate xCT...

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Autores principales:	Wenfei Wang, Yi Cai, Guofang Deng, Qianting Yang, Peijun Tang, Meiying Wu, Ziqi Yu, Fan Yang, Jianyong Chen, Oliver Werz, Xinchun Chen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	xCT polymorphism tuberculosis genotype therapy Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/78f9f0e28da346e482926f2748c704fd
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spelling	oai:doaj.org-article:78f9f0e28da346e482926f2748c704fd2021-11-15T15:29:16ZAllelic-Specific Regulation of xCT Expression Increases Susceptibility to Tuberculosis by Modulating microRNA-mRNA Interactions10.1128/mSphere.00263-202379-5042https://doaj.org/article/78f9f0e28da346e482926f2748c704fd2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00263-20https://doaj.org/toc/2379-5042ABSTRACT xCT forms part of the xc− cysteine-glutamate antiporter which inhibits antimicrobial inflammatory immune functions and thus increases susceptibility to tuberculosis (TB). However, the associations between xCT gene polymorphisms and susceptibility to TB, as well as whether these modulate xCT expression or affect treatment with the xCT inhibitor sulfasalazine (SASP), are unclear. In the present study, we genotyped xCT polymorphisms in a large Chinese cohort and found that the single-nucleotide polymorphism (SNP) rs13120371 was associated with susceptibility to TB. The rs13120371 AA genotype was strongly associated with an increased risk of TB and increased xCT mRNA expression levels compared to those with the GG or AG genotype. rs13120371 is located on the 3′ untranslated (UTR) region of the xCT gene, in the putative binding site for miR-142-3p, and the results of luciferase reporter assays indicated that the rs13120371 AA genotype inhibited the binding of miR-42-3p to xCT. Bacterial burden was also significantly higher in cells with the AA genotype than in those with the GG genotype. Furthermore, pretreatment with SASP alleviated this burden in cells with the AA genotype but conferred no benefit in cells with the GG phenotype. In summary, we identified a functional SNP (rs13120371) in the xCT 3′ UTR region that increases susceptibility to TB through interacting with miR-142-3p. IMPORTANCE Tuberculosis (TB) is the leading cause of death from a single infectious agent globally, and the development of multidrug resistance represents a serious health concern, particularly in the developing world. Novel effective treatments are urgently required. xCT expression is known to increase susceptibility to TB, and certain polymorphisms in the gene encoding this protein interrupt the binding of microRNA and prevent its suppression. Taking advantage of the FDA approval for the use of sulfasalazine (SASP), which inhibits xCT-mediated cystine transport in humans, we demonstrate how host genotype-specific therapies tailored to the xCT genotype can improve TB outcomes.Wenfei WangYi CaiGuofang DengQianting YangPeijun TangMeiying WuZiqi YuFan YangJianyong ChenOliver WerzXinchun ChenAmerican Society for MicrobiologyarticlexCTpolymorphismtuberculosisgenotypetherapyMicrobiologyQR1-502ENmSphere, Vol 5, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	xCT polymorphism tuberculosis genotype therapy Microbiology QR1-502
spellingShingle	xCT polymorphism tuberculosis genotype therapy Microbiology QR1-502 Wenfei Wang Yi Cai Guofang Deng Qianting Yang Peijun Tang Meiying Wu Ziqi Yu Fan Yang Jianyong Chen Oliver Werz Xinchun Chen Allelic-Specific Regulation of xCT Expression Increases Susceptibility to Tuberculosis by Modulating microRNA-mRNA Interactions
description	ABSTRACT xCT forms part of the xc− cysteine-glutamate antiporter which inhibits antimicrobial inflammatory immune functions and thus increases susceptibility to tuberculosis (TB). However, the associations between xCT gene polymorphisms and susceptibility to TB, as well as whether these modulate xCT expression or affect treatment with the xCT inhibitor sulfasalazine (SASP), are unclear. In the present study, we genotyped xCT polymorphisms in a large Chinese cohort and found that the single-nucleotide polymorphism (SNP) rs13120371 was associated with susceptibility to TB. The rs13120371 AA genotype was strongly associated with an increased risk of TB and increased xCT mRNA expression levels compared to those with the GG or AG genotype. rs13120371 is located on the 3′ untranslated (UTR) region of the xCT gene, in the putative binding site for miR-142-3p, and the results of luciferase reporter assays indicated that the rs13120371 AA genotype inhibited the binding of miR-42-3p to xCT. Bacterial burden was also significantly higher in cells with the AA genotype than in those with the GG genotype. Furthermore, pretreatment with SASP alleviated this burden in cells with the AA genotype but conferred no benefit in cells with the GG phenotype. In summary, we identified a functional SNP (rs13120371) in the xCT 3′ UTR region that increases susceptibility to TB through interacting with miR-142-3p. IMPORTANCE Tuberculosis (TB) is the leading cause of death from a single infectious agent globally, and the development of multidrug resistance represents a serious health concern, particularly in the developing world. Novel effective treatments are urgently required. xCT expression is known to increase susceptibility to TB, and certain polymorphisms in the gene encoding this protein interrupt the binding of microRNA and prevent its suppression. Taking advantage of the FDA approval for the use of sulfasalazine (SASP), which inhibits xCT-mediated cystine transport in humans, we demonstrate how host genotype-specific therapies tailored to the xCT genotype can improve TB outcomes.
format	article
author	Wenfei Wang Yi Cai Guofang Deng Qianting Yang Peijun Tang Meiying Wu Ziqi Yu Fan Yang Jianyong Chen Oliver Werz Xinchun Chen
author_facet	Wenfei Wang Yi Cai Guofang Deng Qianting Yang Peijun Tang Meiying Wu Ziqi Yu Fan Yang Jianyong Chen Oliver Werz Xinchun Chen
author_sort	Wenfei Wang
title	Allelic-Specific Regulation of xCT Expression Increases Susceptibility to Tuberculosis by Modulating microRNA-mRNA Interactions
title_short	Allelic-Specific Regulation of xCT Expression Increases Susceptibility to Tuberculosis by Modulating microRNA-mRNA Interactions
title_full	Allelic-Specific Regulation of xCT Expression Increases Susceptibility to Tuberculosis by Modulating microRNA-mRNA Interactions
title_fullStr	Allelic-Specific Regulation of xCT Expression Increases Susceptibility to Tuberculosis by Modulating microRNA-mRNA Interactions
title_full_unstemmed	Allelic-Specific Regulation of xCT Expression Increases Susceptibility to Tuberculosis by Modulating microRNA-mRNA Interactions
title_sort	allelic-specific regulation of xct expression increases susceptibility to tuberculosis by modulating microrna-mrna interactions
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/78f9f0e28da346e482926f2748c704fd
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Allelic-Specific Regulation of xCT Expression Increases Susceptibility to Tuberculosis by Modulating microRNA-mRNA Interactions

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