The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens Original paper

What was reviewed?

This review explains copper and zinc toxicity in innate immunity and how these metals shape early defense against bacteria. It shows that phagocytes load copper and zinc into pathogen-facing spaces, where copper cycles with reactive oxygen and nitrogen species to drive killing and where zinc can disrupt enzymes or starve microbes of manganese. It also outlines how host cells increase CTR1 and ATP7A to raise copper entry and routing, and how ZIP family transporters shift zinc during inflammation. The review links these metal surges to common infection sites, such as the nasopharynx and urinary tract, and to shifts that affect the local microbiome.

Who was reviewed?

The authors synthesize data from human and animal infection models and from primary macrophages and neutrophils. They compare bacterial species that face copper and zinc stress in vivo, including Streptococcus pneumoniae, Salmonella enterica serovar Typhimurium, uropathogenic Escherichia coli, Neisseria gonorrhoeae, Listeria monocytogenes, Mycobacterium tuberculosis, and Helicobacter pylori. They also include work on zinc shifts during fungal infection to show broader innate patterns that can influence mucosal communities.

Most important findings

The review shows that copper and zinc act as direct tools of killing in the phagosome and at mucosal sites. Activated macrophages raise copper import and move ATP7A toward phagolysosomes; copper then amplifies oxidative and nitrosative stress and breaks iron–sulfur enzymes that bacteria need. Bacteria counter with CopA or other P-type ATPases, periplasmic multicopper oxidases such as CueO, and envelope pumps such as CusCFBA; loss of these systems reduces survival in phagocytes and can lower virulence in mice. Zinc acts in two ways: it signals within innate cells and it harms microbes.

At mucosa, elevated zinc blocks manganese uptake in S. pneumoniae and weakens defense against oxidative stress; within phagocytes, zinc efflux mutants such as zntA or czcD show poor intracellular survival. The review notes metal routing in vivo, including higher copper in M. tuberculosis granulomas and copper build-up in urine during uropathogenic E. coli infection. For microbiome catalogs, the metal stress signature spans host transporters (CTR1, ATP7A, ZIP8, ZnT proteins) and microbial resistance loci (copA, cusFCBA, cueO, golT, ctpC, czcD), which map to niches like the nasopharynx, gut, and urinary tract where metals can tilt community structure and pathogen fitness.

Key implications

Clinicians should see copper and zinc handling as a modifiable axis in infection care. Checking nutrition and inflammatory status for these metals can inform risk. Pathogens that carry strong copper or zinc export systems may resist innate metal stress and persist. Adding such loci to a microbiome signatures database can flag strains with higher survival odds in phagocytes or at metal-rich mucosa. Therapies that spare host function yet stress microbial metal control—such as limiting manganese access during zinc surges or timing antibiotics when copper routing peaks—may raise killing while preserving tissue. Any attempt to change metal levels should avoid excess that could harm host cells or widen dysbiosis.