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

## TL;DR

This study shows how the tuberculosis bacterium manipulates a specific RNA to weaken the immune system's defenses and survive in the body.

## Contribution

The paper identifies LINC02528 as a novel lncRNA that Mtb uses to modulate mitochondrial metabolism and immune evasion.

## Key findings

- LINC02528 is upregulated in TB patients and relocates to the cytoplasm during Mtb infection.
- Deleting LINC02528 in macrophages reduces Mtb survival and increases IL-1β production.
- LINC02528 interacts with TOMM22 to suppress glycolysis and ROS, aiding Mtb immune evasion.

## Abstract

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.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), relies on host immune evasion for survival. While oxidative stress is critical for defense, how Mtb disrupts redox balance remains unclear. We discovered a long noncoding RNA, LINC02528, upregulated in TB patients’ immune cells, which relocates during infection. Deleting LINC02528 in macrophages reduced bacterial survival and boosted IL-1β, a key antimicrobial signal. Mechanistically, LINC02528 binds TOMM22, a mitochondrial protein, to suppress glycolysis and reactive oxygen species (ROS)—helping Mtb evade immunity. Strikingly, blocking TOMM22 mimicked LINC02528 loss, confirming their shared role in metabolic hijacking. Our work reveals how Mtb exploits the LINC02528-TOMM22 axis to weaken host defenses. Targeting this pathway could starve Mtb of its redox shelter while activating IL-1β-driven immunity, offering a dual-action strategy against TB.