Mycobacterium tuberculosis and Copper: A Newly Appreciated Defense against an Old Foe? Original paper

What was reviewed?

This review explains Mycobacterium tuberculosis and copper as a host–pathogen battle in which the host raises copper to hurt the bacillus, while the bacillus builds defenses to survive. It maps copper sources in infection, such as ATP7A-driven copper delivery to phagosomes and possible release from ceruloplasmin, and then details the mycobacterial systems that sense, export, or buffer copper. Chief units include the CsoR regulon with the putative exporter CtpV, the RicR regulon with the metallothionein MymT and the multicopper oxidase MmcO, and the membrane protein MctB that prevents toxic copper build-up. Together, these data show how copper acts as nutritional immunity against tuberculosis and how gene circuits help the bacillus persist.

Who was reviewed?

The review covers M. tuberculosis copper responses tested across broth, macrophage models, and animal infections in mice and guinea pigs, and it links them to host copper routing in phagocytes. It integrates transcript data that defined CsoR and RicR regulons, deletion studies for ctpV, mymT, mmcO, and mctB, and fitness tests in vivo that showed stronger defects in guinea pigs than in mice for key mutants. It also discusses possible copper entry through porins and notes that mycobacteria keep far less cytosolic copper than environmental relatives. On the host side, it highlights ATP7A as a phagosomal copper pump and proposes ceruloplasmin as a copper source that phagocytes can process. This multi-system view ties gene function to real tissue niches where copper rises around bacilli.

Most important findings

The review concludes that copper rises at infection sites and that M. tuberculosis needs several copper defenses for full virulence. The CsoR–ctpV pathway supports copper export and contributes to virulence in guinea pigs. The RicR regulon turns on mymT (a Cu(I)-binding metallothionein), mmcO (a membrane-anchored multicopper oxidase), and other genes; single mymT or mmcO mutants show copper sensitivity in vitro but no mouse virulence loss, while a RicR “Cu-blind” strain that keeps the regulon off becomes copper-sensitive and attenuated. MctB limits intracellular copper; loss of mctB causes copper accumulation, strong copper sensitivity, and marked attenuation in mice and guinea pigs, with copper-supplemented hosts worsening the defect. The paper also points to ATP7A-dependent copper delivery by macrophages as a likely antimicrobial route and notes that acidic phagolysosomes may keep copper in its most toxic form.

Key implications

Clinicians can treat copper handling as a virulence trait and as part of nutritional immunity. In a microbiome signatures database, flag Mycobacterium tuberculosis and copper with markers that include mctB (low intracellular copper), ctpV (export), mymT/mmcO (buffering/oxidation), and host ATP7A at phagosomes. The presence and regulation of these loci predict survival in copper-rich lesions and help explain why copper exposure in granulomas suppresses bacilli. Therapeutic ideas include small molecules that inhibit MctB or keep the RicR regulon off, which would sensitize bacilli to physiologic copper and work with immunity rather than replace it. Any copper-targeted step should balance pathogen control against host toxicity and consider tissue site, inflammation, and pH, which shape copper speciation and effect