A vaccine protein hides mitochondrial DNA and weakens trained immunity

Tuberculosis remains a global threat, and scientists are trying to understand how vaccines like Bacillus Calmette-Guérin (BCG) shape long-term immunity in frontline immune cells called macrophages. Traditionally, research on innate immune memory has focused on nuclear chromatin remodeling and histone changes that control gene transcription. In work led by Baoxue Ge, researchers looked beyond the nucleus to the mitochondria — the cell’s energy factories — asking whether the mitochondrial genome itself could set the functional state of trained macrophages. Rather than reporting new drug trials, this study traced how mitochondrial DNA (mtDNA) accessibility and organization affect macrophage responses. The team found that the abundance of mitochondrial transcription factor A (TFAM) and a process they call mtATP-dependent remodeling determine whether mtDNA is compacted or open, and that this state in turn shapes the ability of macrophages to mount boosted responses to secondary infections. The study connects a specific BCG component to these mitochondrial changes, offering a fresh view of how vaccines can either promote or restrain protective immunity.

The researchers show that mtDNA compaction is governed by TFAM abundance together with mtATP-dependent remodeling, and that this compaction defines the transcriptional and functional state of trained macrophages. Typical pathogen-associated molecular pattern (PAMPs) increased mtDNA accessibility, but the Bacillus Calmette-Guérin (BCG) effector PE18 acted differently: PE18 directly interacted with and activated SLC25A5, which reduced mtATP levels. Lower mtATP inhibited degradation of TFAM by AFG3L2, causing TFAM to accumulate. Accumulated TFAM restricted mtDNA accessibility and suppressed transcription of the mitochondrial gene mtNd1, which in turn reduced mtNd1-mediated mtROS production. The drop in mtROS diminished the trained capacity of macrophages against secondary infections. Importantly, a BCG strain lacking this factor, BCGΔ pe18, maintained macrophage cytokine transcriptional capacity independent of classical nuclear histone modifications. Moreover, BCGΔ pe18 provided robust and lifelong protective immunity against Mycobacterium tuberculosis ( Mtb ) infection in the study’s models.

These findings reframe the mitochondrial genome as a regulatory entity in trained immunity and point to new levers for improving vaccine performance. By showing that a single bacterial effector, PE18, can trigger a cascade — SLC25A5 activation, reduced mtATP, blocked AFG3L2-mediated TFAM degradation, mtDNA compaction, lowered mtNd1 expression and less mtROS — the work highlights multiple molecular steps that determine whether macrophages become more or less responsive to later infections. The fact that BCGΔ pe18 preserved cytokine transcription and delivered strong, long-lived protection against Mycobacterium tuberculosis ( Mtb ) suggests that removing or neutralizing similar effectors could make vaccines more effective. More broadly, targeting mitochondrial factors such as TFAM stability or mtATP dynamics might be a strategy to tune trained immunity without altering classical nuclear histone pathways, offering a complementary route to enhance immune protection against tuberculosis and possibly other infections.