Epigenetic changes weaken T cell genes in pulmonary tuberculosis

Researchers led by corresponding author Indu Verma set out to understand how the host immune system is changed at the molecular level during active pulmonary tuberculosis (PTB). The study builds on growing evidence that infection by pathogens can drive promoter hypermethylation of host genes, an epigenetic change that can reduce gene activity without altering DNA sequence. To investigate whether such epigenetic reprogramming affects immune response genes in TB, the team analyzed genome-wide DNA methylation patterns in peripheral blood mononuclear cells (PBMCs). Their stated objective was to elucidate the differential genome-wide DNA methylation profile of PBMCs in PTB patients compared with healthy and diseased controls. The design compared three study groups—PTB, healthy controls, and diseased controls—using matched sample preparation and sequencing workflows to focus on methylation differences that might be tied to disease-associated changes in immune function.

To decipher methylation patterns the investigators performed whole genome bisulphite sequencing after bisulphite conversion and library preparation on 4 DNA samples from each study group (PTB, healthy controls, diseased controls). Data analysis included differential methylation region (DMR) analysis and gene set enrichment analysis to identify regions for validation by sanger sequencing. The DMR analysis produced counts of hypermethylated and hypomethylated regions for each comparison: TB v/s Diseased (Hypermethylated=1756; Hypomethylated=1886), TB v/s Healthy( Hypermethylated=2203; Hypomethylated=2466), Diseased v/s Healthy ( Hypermethylated=1656; Hypomethylated=3936). Gene set enrichment analysis showed that hypermethylated regions were enriched in genes involved in immune responses, mainly T cell functioning and T cell mediated immune processes. Eight DMRs mapped simultaneously to TAF8, FZD5, HLA-DRB, MIR483, PVRIG, SH2B2, ZAP70, TNFRSF13C (n=10 from each study group). The online server GEOR2 (Datasets used n= 12) was used to examine mRNA expression and revealed significant downregulation of TNFRSF13C, ZAP70, and PVRIG among the selected genes associated with hypermethylated promoter DMRs.

Taken together, the findings reported by Indu Verma and colleagues indicate that active pulmonary tuberculosis is associated with altered methylation patterns in PBMCs, and that these changes concentrate on genes that regulate T cell responses. The study concludes that aberrant methylation of expression-regulating regions occurs on disease onset and is linked to decreased T cell functions and suboptimal immune responses in TB. In plain terms, the immune system’s T cells may be less able to respond effectively because key regulatory genes show increased methylation and lower mRNA expression. While this work does not by itself prove cause and effect, it provides a molecular snapshot that connects epigenetic reprogramming with impaired T cell-related gene activity in PTB. The results point toward further research to validate these DMRs, to understand timing during infection, and to explore whether reversing methylation or monitoring these changes could help explain or track the immune dysfunction seen in active TB.