Targeting PU.1: a new host-directed strategy against tuberculosis

Mycobacterium tuberculosis (Mtb) is known to change the behavior of the immune cells it infects. In work led by Jérémie Poschmann, researchers set out to find which factors in human immune cells control those changes. They focused on monocytes and macrophages, two cell types that respond to Mtb infection, and looked specifically at how the infection alters the chemical markings and activity that control genes. Using an integrative approach, the team examined chromatin modification, transcription factor binding and gene expression to identify the key drivers of the cell's response. Their search revealed a transcription factor called PU.1 (SPI1) as a prominent signal that increases after infection and attaches to many gene promoters. The discovery points to PU.1 as a central player in how human immune cells reprogram themselves when faced with Mtb and set the stage for testing whether changing PU.1 activity could affect the course of infection.

To pin down the role of PU.1 (SPI1), the researchers combined measurements of chromatin modification (H3K27ac), transcription factor binding and gene expression in human monocytes and macrophages exposed to Mtb. These integrative analyses showed that PU.1 was upregulated and enriched at gene promoters in infected cells. PU.1 enrichment correlated with the activation of proinflammatory genes and anti-apoptotic gene programs, patterns that can keep infected cells alive and inflamed. The team also checked lung tissue and found PU.1 expression elevated in Mtb-infected macaques and in tuberculosis patients, reinforcing the connection to disease. To test function, they reduced PU.1 levels using knockdown experiments in human macrophages and observed more apoptosis, reduced inflammatory signaling, and lower survival of Mtb. Importantly, pharmacological inhibition of PU.1 reproduced the knockdown effects and restricted Mtb growth without causing cytotoxicity, demonstrating a laboratory proof of principle that targeting PU.1 can alter infection outcomes.

These findings identify PU.1 (SPI1) as a central node in the host epigenetic response to Mtb and point to a different therapeutic idea: instead of directly attacking the bacterium, modify the host response that the bacterium exploits. Because PU.1 enrichment was tied to proinflammatory and anti-apoptotic programs and because both genetic knockdown and pharmacological inhibition reduced bacterial survival without killing host cells, PU.1 becomes a candidate for host-directed therapy in tuberculosis. That approach could potentially shift how infected cells behave, making the environment less hospitable to Mtb. At the same time, the results are early and laboratory-based; translating this into safe, effective treatments will require careful development of inhibitors, testing for unintended effects, and clinical studies to confirm benefit in patients.