Copper resistance is essential for virulence of Mycobacterium tuberculosis Original paper

Researched by:

  • Divine Aleru ID
    Divine Aleru

    User avatarI am a biochemist with a deep curiosity for the human microbiome and how it shapes human health, and I enjoy making microbiome science more accessible through research and writing. With 2 years experience in microbiome research, I have curated microbiome studies, analyzed microbial signatures, and now focus on interventions as a Microbiome Signatures and Interventions Research Coordinator.

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September 3, 2025

  • Metals
    Metals

    OverviewHeavy metals play a significant and multifaceted role in the pathogenicity of microbial species. Their involvement can be viewed from two primary perspectives: the toxicity of heavy metals to microbes and the exploitation of heavy metals by microbial pathogens to establish infections and evade the host immune response. Understanding these aspects is critical for both […]

  • Microbes
    Microbes

    Microbes, short for microorganisms, are tiny living organisms that are ubiquitous in the environment, including on and inside the human body. They play a crucial role in human health and disease, functioning within complex ecosystems in various parts of the body, such as the skin, mouth, gut, and respiratory tract. The human microbiome, which is […]

Researched by:

  • Divine Aleru ID
    Divine Aleru

    User avatarI am a biochemist with a deep curiosity for the human microbiome and how it shapes human health, and I enjoy making microbiome science more accessible through research and writing. With 2 years experience in microbiome research, I have curated microbiome studies, analyzed microbial signatures, and now focus on interventions as a Microbiome Signatures and Interventions Research Coordinator.

    Read More

Last Updated: 2025-09-03

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Divine Aleru

I am a biochemist with a deep curiosity for the human microbiome and how it shapes human health, and I enjoy making microbiome science more accessible through research and writing. With 2 years experience in microbiome research, I have curated microbiome studies, analyzed microbial signatures, and now focus on interventions as a Microbiome Signatures and Interventions Research Coordinator.

What was studied?

This original study tested the claim that copper resistance is essential for the virulence of Mycobacterium tuberculosis by defining how the outer membrane channel MctB (Rv1698) prevents toxic copper build-up and supports survival in vivo. The authors combined genetics, metal quantification, and animal infection models to link copper handling to disease. They deleted mctB, restored it by complementation, and measured copper inside cells, growth under copper stress, and bacterial fitness during infection. They also showed that host tissues increase copper in granulomas, suggesting that the immune system uses copper to restrict the pathogen. The work frames copper as both a nutrient and a weapon and positions MctB as a key defense that maintains low intracellular copper and protects the bacillus from phagosomal copper spikes.

Who was studied?

Researchers worked with Mycobacterium tuberculosis H37Rv and an isogenic ∆mctB mutant, plus a complemented strain. They used M. smegmatis to confirm conserved function of the homolog Ms3747. For in vivo tests, they infected BALB/c mice and guinea pigs with low-dose aerosols and, in mice, raised dietary copper to mimic higher host copper exposure. They microdissected guinea pig lung granulomas to measure tissue copper and tracked organism burden in lungs, lymph nodes, and spleen. Across these settings they quantified intracellular copper, copper-responsive gene signals, and survival to connect MctB function with virulence during host copper stress.

Most important findings

Loss of MctB caused striking copper sensitivity and accumulation. The ∆mctB mutant accumulated about two orders of magnitude more intracellular copper and showed severe growth inhibition at copper levels tolerated by wild type; a copper(I) chelator rescued growth, marking Cu(I) as the toxic species. In mice, copper supplementation sharpened the mutant’s survival defect, consistent with copper-driven killing. In guinea pigs, copper concentrations rose within primary lung granulomas, and ∆mctB displayed a profound virulence defect with roughly 1,000-fold fewer bacteria in lungs and 100-fold fewer in lymph nodes than wild type at day 30, despite preserved granuloma histology. These results reveal a clean microbial signature in which MctB-mediated efflux limits intracellular copper, while host tissues raise copper at infection sites to suppress bacilli. They also show that M. tuberculosis is unusually copper-sensitive compared with many bacteria, with inhibitory copper levels matching those found in phagosomes.

Key implications

Clinicians can treat copper handling as a virulence trait in tuberculosis. Genomic detection of mctB in a microbiome signatures database should flag strains with stronger capacity to endure host copper stress, while absence or dysfunction of this locus predicts impaired survival when granulomas elevate copper. Because copper levels in phagosomes approach those that inhibit M. tuberculosis, drugs that block MctB could sensitize bacilli to physiologic copper and work as immune-boosting adjuncts rather than direct bactericides. In settings where diet or inflammation raises tissue copper, failure of copper efflux may reduce pathogen fitness, but host injury from excess copper remains a concern; any copper-targeted strategy should balance pathogen control against host toxicity. Embedding mctB with other copper loci (e.g., ctpV, mymT) and host copper routing markers in reports can help link tissue site, inflammation state, and predicted bacterial persistence, supporting risk stratification and targeted therapy.

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