Identification of MicroRNAs as Potential Blood-Based Biomarkers for Diagnosis and Therapeutic Monitoring of Active Tuberculosis

Abstract

Early diagnosis increases the treatment success rate for active tuberculosis (ATB) and decreases mortality. MicroRNAs (miRNAs) have been studied as blood-based markers of several infectious diseases. We performed miRNA profiling to identify differentially expressed (DE) miRNAs using whole blood samples from 10 healthy controls (HCs), 15 subjects with latent tuberculosis infection (LTBI), and 12 patients with ATB, and investigated the expression of the top six miRNAs at diagnosis and over the treatment period in addition to performing miRNA-target gene network and gene ontology analyses. miRNA profiling identified 84 DE miRNAs in patients with ATB, including 80 upregulated and four downregulated miRNAs. Receiver operating characteristic curves of the top six miRNAs exhibited excellent distinguishing efficiency with an area under curve (AUC) value > 0.85. Among them, miR-199a-3p and miR-6886-3p can differentiate between ATB and LTBI. Anti-TB treatment restored the levels of miR-199b-3p, miR-199a-3p, miR-16-5p, and miR-374c-5p to HC levels. Furthermore, 108 predicted target genes were related to the regulation of cellular amide metabolism, intrinsic apoptotic signaling, translation, transforming growth factor beta receptor signaling, and cysteine-type endopeptidase activity. The DE miRNAs identified herein are potential biomarkers for diagnosis and therapeutic monitoring in ATB.

p50-associated Cyclooxygenase-2 Extragenic RNA (PACER) and Long Non-coding RNA 13 (LNC13) as potential biomarkers for monitoring tuberculosis treatment

“…Wagh et al (2017) also reported that miR-16 expression levels in sera of TB patients who received the standard anti-TB drug regimen for six months increased to reach the approximate level of healthy controls (52). Similarly, Kim et al (2022) found that the levels of miR-199b-3p, miR-199a-3p, and miR-16-5p were restored to healthy controls levels after standard anti-tuberculosis therapy (53).…”

MicroRNAs as immune regulators and biomarkers in tuberculosis

“…Five downregulated miRNAs (miR-326, miR-346, miR-21-5p, miR-92a-3p, and miR-148b-3p) were identified in serum ( 199 , 220 , 221 ). Studies have shown that the miR-199b-3p, miR-199a-3p, and miR-16-5p levels in whole blood and the miR-424 levels in PBMCs are significantly decreased ( 222 , 223 ). Increased miR-125a-5p levels were observed in TB patients who were treated for 2 months ( 221 ).…”

“…Based on miRNA upregulation and downregulation in LTBI and TB, 39 miRNAs are divided into eight categories. Ten miRNAs (miR-1246, miR-2110, miR-370-3p, miR-28-3p, miR-193b-5p, let-7b-5p, miR-30b-5p, miR-424, miR-365, and 199a-3p) are upregulated only in TB patients ( 223 , 236 – 238 ). Five miRNAs (miR-374a, miR-26a, miR-142-3p, miR-16-5p, and miR-451a) are downregulated only in TB patients ( 103 , 239 , 240 ).…”

“…miR-150 and miR-146a expression is decreased in patients with TB and LTBI ( 222 , 239 ). Of course, there are miRNAs (miR-29a-3p, miR-361-5p, miR-196b, miR-451a, miR-340-5p, miR-199b-3p, miR-6856-3p, miR-16-5p, miR-374c-5p, miR-6886-3p, and miR-378) whose expression is increased in both patients with TB and LTBI ( 218 , 223 , 242 – 244 ). The number of miRNAs with elevated expression in LTBI and TB is higher, which may be caused by the host immune response to pathogen infection.…”

Under diagnosis of tuberculosis in times of pandemic and the use of microRNAs as biomarkers of infection

“…One of the most promising tools for the diagnosis and therapeutic followup of patients is the use of microRNAs as biomarkers of infectious diseases in blood. 35,36 miRNAs are small, non-coding RNAs, typically 18-24 nucleotides in size, that have an important role in regulating gene expression at the post-transcriptional level and are involved in shaping immunity by regulating gene expression in immune cells. To carry out their regulatory activities, miRNAs bind to their complementary sequence at the 3'untranslated end of the messenger RNA, targeting it for degradation or inhibiting its translation.…”