PU.1 Shapes Host Epigenetic Responses to Mycobacterium tuberculosis and Represents a Target for Host Directed Therapy

Mycobacterium tuberculosis ( Mtb ) infection induces widespread epigenetic changes in monocytes and macrophages. To characterize the critical factor responsible for Mtb -induced epigenetic responses, we performed an integrative analyses of chromatin modification (H3K27ac), transcription factor binding, and gene expression in human monocytes and macrophages. Our data identified PU.1 (SPI1) as a key transcriptional regulator to be upregulated and bound to gene promoters in response to Mtb . PU.1 enrichment was associated with enhanced proinflammatory and anti-apoptotic gene programs. PU.1 expression was also elevated in the lung tissues from Mtb -infected macaques and tuberculosis patients. PU.1 knockdown enhanced human macrophage apoptosis, dampened inflammation and reduced bacterial survival, suggesting its functional role in supporting Mtb infection. Pharmacological inhibition of PU.1 replicated the effects of knockdown, restricting Mtb growth without cytotoxicity. These findings identify PU.1 as a central node in the host epigenetic response to Mtb and a candidate for host-directed therapeutic targeting in tuberculosis.