Induction of mitochondrial DNA compaction limits innate immune memory

Implication of innate immune memory in host defense and pathogenesis of diverse inflammatory diseases is usually characterized by chromatin modification that leads to more effective transcription of cytokine genes. Mitochondrial DNA (mtDNA) is compacted by mitochondrial transcription factor (TFAM) and plays a crucial role in maintaining mitochondrial function. Here, we demonstrate that Bacillus Calmette-Guérin (BCG) PE18 induced mtDNA compaction through enhancing TFAM level. Mechanistically, PE18 interacted with SLC25A5 and reduced mitochondrial ATP level, thus blocking the degradation of TFAM by protease AFG3L2. Accumulated TFAM restricted mtDNA accessibility, which inhibited transcription of mitochondrial encoded NADH dehydrogenase subunit 1 (mtNd1), leading to reduction of oxidative phosphorylation (OXPHOS) activity and mtROS production. Moreover, deletion of pe18 from BCG conferred better and longer protection against Mycobacterium tuberculosis (Mtb) infection, and higher safety in immunocompromised mice than did parental BCG. These findings suggest that targeting mtDNA accessibility for immune memory may provide prevailing protective immunity.