Mycobacterium tuberculosis manipulates LINC02528 in macrophages to modulate anti-tuberculosis metabolic immunity.

Host defenses are crucial in deciding the fate of Mycobacterium tuberculosis (Mtb) infections, as less than 10% of infected individuals develop tuberculosis. Oxidative stress plays a critical role in the host defense against Mtb. However, the mechanisms by which Mtb modulates redox homeostasis to evade immune responses remain poorly understood. In this study, we primarily identified a pathogen-responsive long noncoding RNA, LINC02528, which was selectively upregulated in peripheral blood mononuclear cells (PBMCs) from tuberculosis (TB) patients. In Mtb-infected macrophages, LINC02528 dynamically relocalizes from the nucleus to the cytoplasm. Functionally, CRISPR-Cas9-mediated knockout (KO) of LINC02528 in macrophages resulted in reduced Mtb survival concurrent with an elevated IL-1β expression. Importantly, these antimicrobial effects were abrogated by IL-1 receptor antagonist (IL-RA) treatment. Interestingly, LINC02528 was found to directly bind to TOMM22, a mitochondrial outer membrane translocase, as validated by co-localization analysis using in situ hybridization of lung tissue sections from a TB patient. The ECAR results revealed that LINC02528 deficiency significantly increased glycolysis and elevated Mtb-induced mitochondrial ROS (mtROS) production. Notably, TOMM22 knockdown phenocopied LINC02528 deletion effects, suggesting functional interdependence in modulating mitochondrial dynamics and the host's anti-TB immunity. Collectively, our findings reveal a novel strategy wherein Mtb hijacks the lncRNA-mitochondrial axis to rewire redox-metabolic checkpoints to favor immune evasion. Targeting LINC02528 could dually disrupt the pathogen-permissive redox balance and activate mtROS-IL-1β-mediated antimicrobial defense, offering novel therapeutic avenues for TB.