Infected immune cells send signals that prime cells to fight tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of death from infectious disease, and researchers are working to understand how the immune system can be better prepared to fight it. Infected immune cells do not act in isolation: they secrete extracellular vesicles (EVs), nanosized membrane-bound particles that carry proteins and other bioactive molecules and help cells communicate. Maria Lerm and her team set out to test whether EVs produced by macrophages infected with Mycobacterium bovis Bacillus Calmette Guérin (BCG) could change the behavior of nearby naïve monocytes and make those recipient macrophages better at killing Mtb. To study this, the investigators used a transwell co-culture system that lets cells exchange EVs and soluble factors without direct contact, enabling them to isolate the impact of signals released by BCG-infected macrophages. The work focuses on epigenetic reprogramming—stable changes in gene activity that are not caused by changes in DNA sequence—and whether those changes translate into improved control of Mtb in laboratory tests.

The team examined both the particles released by infected cells and the molecular changes in the cells that received those particles. They found that BCG-infected macrophages released EVs with a distinct proteomic profile, meaning the protein cargo of those EVs mapped to multiple tuberculosis-related pathways. Using the transwell co-culture system, researchers compared recipient macrophages exposed to EVs and soluble factors from BCG-infected cells with recipient cells co-cultured with untreated macrophages, Staphylococcus aureus-infected macrophages, or macrophages exposed to hydrogen peroxide. Recipient macrophages exposed to the BCG-derived signals showed altered DNA methylation patterns compared to these controls. The proteomic cargo of the EVs and the differentially methylated genes in recipient cells showed significant interactions centered on TNF as a hub, with enrichment in the phagosome and tuberculosis pathway. This epigenetic reprogramming was accompanied by a trend toward improved control of Mtb in vitro, suggesting the signals have functional consequences.

Taken together, these findings indicate that infected macrophages can transmit epigenetic information to nearby immune cells via EVs and soluble factors, producing targeted remodeling of DNA methylation and associated changes in pathways linked to TB. The study shows that the proteins carried by EVs are not random debris but have a directed proteomic cargo that interacts with genes in recipient cells, with TNF emerging as a central node in relevant immune pathways. While the work is preclinical and described in laboratory cultures, it offers new insight into how intercellular communication can contribute to innate immune memory—an ability of the innate immune system to respond differently after prior exposure. These insights may guide future research exploring whether manipulating EV signals or the resulting epigenetic changes could become part of strategies to strengthen mycobactericidal activity or inform vaccine-related research, although further studies are needed to translate these findings into clinical applications.