The role of programmed cell death pathways in the host response to Mycobacterium tuberculosis: Insights from gene expression analysis in active pulmonary tuberculosis patients.

Tuberculosis, primarily caused by Mycobacterium tuberculosis (Mtb), remains a leading global health issue. We investigate the interplay between Mtb infection and various programmed cell death (PCD) in active pulmonary tuberculosis (ATB). Using GSE19491 and GSE107994 datasets, we identified 1306 overlapping differentially expressed genes (DEGs) in peripheral blood from ATB patients and healthy controls. Gene set variation analysis revealed that, except for cuproptosis, the PCD pathways: necroptosis, apoptosis, pyroptosis, and ferroptosis were significantly elevated in ATB patients. Weighted Gene Co-expression Network Analysis further identified 392 PCD-associated hub genes. KEGG and GO analyses highlighted key functional enrichments in immune responses, cellular stress, and PCD pathways. Moreover, we found a positive correlation between PCD types and specific immune cell populations. Additionally, by integrating DEGs of peripheral blood samples and lung granuloma tissues with PCD-associated hub genes, we identified 30 PCD-related genes in ATB patients. RT-qPCR results demonstrated significantly elevated GCLC, RBCK1, ZEB1, and EIF2AK2 levels, alongside lowered PLA2G4C and CAMK2G levels in patients' peripheral blood. These findings underscore the critical role of PCD pathways in modulating the immune response during Mtb infection. Future mechanistic studies are required to definitively establish the causal roles of these pathways in regulating cell death and bacterial control.