How an antidepressant helps immune cells fight tuberculosis

Tuberculosis remains a major killer worldwide, in part because the bacteria that cause it, Mycobacterium tuberculosis (Mtb), live inside immune cells called macrophages and are hard to clear. In work led by Vivek Rao, researchers looked inside those macrophages to understand how their metabolism affects the fight against Mtb. Rather than targeting the bacterium directly, the team asked whether changing the host cell’s metabolism could make macrophages better killers. They focused on cholesterol, a key cellular lipid that affects many membrane processes, and tested sertraline (SRT), an FDA-approved antidepressant known to be a cationic amphiphilic drug (CAD). The study found that SRT causes cholesterol to build up in lysosomes—cell compartments that break down material—and triggers a chain of events inside macrophages that ultimately improves bacterial control. By tracing these steps, the team uncovered a surprising link between cholesterol handling and activation of the inflammasome, a protein complex that helps macrophages kill microbes. This reframing of tuberculosis therapy looks beyond antibiotics and toward host-directed strategies that boost immune function.

The researchers explored the mechanism behind SRT’s effect using a combination of cellular assays and targeted interventions. They report that sertraline’s cationic amphiphilicity causes lysosomal cholesterol accumulation and that this is associated with NPC1 inhibition. That disturbance in cholesterol trafficking leads to activation and processing of the transcription factor SREBP2, driving enhanced cholesterol biosynthesis. By specific gene silencing and biochemical inhibition assays they showed that these changes promote lysosomal membrane permeabilization and increased mitochondrial reactive oxygen species (ROS) generation. Those mitochondrial signals were accompanied by heightened IL-1β release and activation of NLRP3 signalling, linking cholesterol mishandling to inflammasome activation. Together these responses enhanced macrophage bactericidal activity against Mtb. The authors also compared sertraline’s actions to other CADs and distinguished sertraline’s cholesterol-sequestering activity as the mechanistic basis for its host-directed effect.

These findings point to macrophage cholesterol homeostasis as a central lever for improving anti-tubercular therapy. By establishing cholesterol sequestration via NPC1 inhibition and downstream SREBP2 processing as the pathway by which sertraline enhances bacterial clearance, the work provides a clear mechanistic framework for host-directed adjuncts. Because sertraline is already FDA-approved, the study raises the possibility of repurposing it or similar cholesterol-modulating agents to boost immune clearance alongside antibiotics, although clinical evaluation would be required. Beyond sertraline itself, the results should help researchers screen and design new adjunctive compounds that specifically modulate cholesterol trafficking to trigger lysosomal membrane changes, mitochondrial ROS, and NLRP3-driven inflammasome responses. Ultimately, targeting host cholesterol pathways could become a complementary strategy to shorten or strengthen tuberculosis treatment regimens and reduce the burden of persistent infection.