Mycobacterium marinum MMAR_0267-regulated copper utilization facilitates bacterial escape from phagolysosome

The host limits Mycobacterium tuberculosis ( Mtb ) by restricting copper access. This research investigates how Mtb escapes copper stress. The membrane protein encoded by Mtb Rv0102 , when its homolog in M. smegmatis ( MSMEG_4702 ) was knocked out, resulted in a fourfold decrease in intracellular copper levels and enhanced tolerance to elevated extracellular copper concentrations. Similarly, knockout mutants of its homolog in M. marinum ( MMAR_0267 ) showed increased virulence in zebrafish and higher bacterial load within macrophages. In THP-1 cells infected with MMAR_0267 deletion mutants, the intracellular survival of the mutants increased, accompanied by reduced THP-1 apoptosis. Cu deficiency down-regulated the transcriptional level of the M. marinum virulence factor CFP-10, dampened macrophage STING cytosolic signaling, resulting in decreased IFN-β production and cell apoptosis. In conclusion, these findings highlight the significant impact of copper on the survival and reproduction of mycobacteria, underscoring the importance of studying mycobacterial adaptation mechanisms in copper-rich environments.