Madamarandawala Pavithra, Rajapakse Sanath, Gunasena Bandu, Madegedara Dushantha, Magana-Arachchi Dhammika
Molecular Microbiology & Human Diseases Project, National Institute of Fundamental Studies, Hantana Road, Kandy, 20000, Sri Lanka.
Department of Molecular Biology and Biotechnology, Faculty of Science, University of Peradeniya, Peradeniya, 20400, Sri Lanka.
Mol Biol Rep. 2023 Apr;50(4):3935-3943. doi: 10.1007/s11033-023-08307-6. Epub 2023 Feb 7.
Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis is one of the top thirteen causes of death worldwide. The major challenge to control TB is the emergence of drug-resistant tuberculosis (DR-TB); specifically, multi-drug resistant TB which are resistant to the most potent drugs; rifampin and isoniazid. Owing to the inconsistencies of the current diagnostic methods, a single test cannot identify the whole spectrum of DR-TB associated mutations. Recently, host blood transcriptomics has gained attention as a promising technique that develops disease-specific RNA signatures/biomarkers. However, studies on host transcriptomics infected with DR-TB is limited. Herein, we intended to identify genes/pathways that are differentially expressed in multi-drug/rifampin resistant TB (MDR/RR-TB) in contrast to drug susceptible TB.
We conducted blood RNA sequencing of 10 pulmonary TB patients (4; drug susceptible and 6; DR-TB) and 55 genes that were differentially expressed in MDR/RR-TB from drug-susceptible/mono-resistant TB were identified. CD300LD, MYL9, VAMP5, CARD17, CLEC2B, GBP6, BATF2, ETV7, IFI27 and FCGR1CP were found to be upregulated in MDR/RR-TB in all comparisons, among which CLEC2B and CD300LD were not previously linked to TB. In comparison pathway analysis, interferon alpha/gamma response was upregulated while Wnt/beta catenin signaling, lysosome, microtubule nucleation and notch signaling were downregulated.
Up/down-regulation of immunity related genes/pathways speculate the collective effect of hosts' attempt to fight against continuously multiplying DR-TB bacteria and the bacterial factors to fight against the host defense. The identified genes/pathways could act as MDR/RR-TB biomarkers, hence, further research on their clinical use should be encouraged.
由结核分枝杆菌引起的结核病是全球前13位死因之一。控制结核病的主要挑战是耐药结核病（DR-TB）的出现；特别是对最有效的药物利福平和平阳霉素耐药的耐多药结核病。由于目前诊断方法的不一致性，单一检测无法识别与DR-TB相关的所有突变。最近，宿主血液转录组学作为一种有前途的技术受到关注，该技术可开发疾病特异性RNA特征/生物标志物。然而，关于DR-TB感染的宿主转录组学研究有限。在此，我们旨在识别与药物敏感结核病相比，在耐多药/利福平耐药结核病（MDR/RR-TB）中差异表达的基因/通路。
我们对10例肺结核患者（4例药物敏感，6例DR-TB）进行了血液RNA测序，并鉴定了55个在MDR/RR-TB中与药物敏感/单耐药结核病差异表达的基因。在所有比较中，发现CD300LD、MYL9、VAMP5、CARD17、CLEC2B、GBP6、BATF2、ETV7、IFI27和FCGR1CP在MDR/RR-TB中上调，其中CLEC2B和CD300LD以前未与结核病相关联。在比较通路分析中，干扰素α/γ反应上调，而Wnt/β连环蛋白信号、溶酶体、微管成核和Notch信号下调。
免疫相关基因/通路的上调/下调推测了宿主对抗不断繁殖的DR-TB细菌的尝试以及细菌对抗宿主防御的因素的共同作用。所鉴定的基因/通路可作为MDR/RR-TB生物标志物，因此，应鼓励对其临床应用进行进一步研究。
