Inflammatory immunity and bacteriological perspectives: A new direction for copper treatment of sepsis Original paper

What was reviewed?

This review examines copper treatment of sepsis and explains how copper shapes the host–pathogen fight from the gut to the bloodstream. The review describes copper as both a cofactor for life and a toxic stressor that immune cells deploy in phagosomes. It outlines copper’s links to apoptosis, pyroptosis, necroptosis, ferroptosis, and cuproptosis, and shows how these death pathways influence inflammation, barrier injury, and organ damage during sepsis. It also summarizes emerging therapeutic ideas, including copper chelators, copper ionophores, and copper-based nanomaterials, while warning that dose and timing matter because excess copper can worsen oxidative stress and tissue injury. The review connects these mechanisms to clinical signals, noting that blood copper levels rise in sepsis and may track risk.

Who was reviewed?

The authors synthesize findings from human cohorts with sepsis, animal models, and cell systems that profile copper handling in immune cells and epithelia. They integrate bacteriological data across major pathogens that face copper stress in the host, including Gram-negative organisms such as Salmonella and Escherichia coli, and Gram-positive organisms such as Staphylococcus aureus and Streptococcus pneumoniae. They also discuss mycobacteria and fungal models where copper transport and metalloregulation influence virulence. Across these sources, the review maps host importers and pumps that load copper into phagolysosomes, and microbial copper resistance modules and oxidases that keep periplasmic and cytosolic copper in check during infection.

Most important findings

The host raises copper at infection sites and in activated macrophages, where copper works with nitric oxide and reactive oxygen species to damage invading cells; chelating host copper reduces killing in models, confirming causality. Pathogens counter with P1B-type ATPase exporters, periplasmic multicopper oxidases, copper chaperones, and metallothioneins, and loss of these systems reduces survival in macrophages and lowers virulence in vivo. In the intestine, enterocyte ferroptosis and barrier loss can drive bacterial translocation in sepsis, linking metal stress to microbiome disruption. In patients, copper levels and the copper-to-zinc ratio associate with outcomes, suggesting biomarker potential. Copper ionophores, chelators, and copper nanomaterials show antibacterial and immuno-modulating effects in preclinical sepsis, including reactive species control and improved organ injury, but over-exposure can amplify inflammation and apoptosis. Together, these data position microbial copper resistance genes and host copper routing as key microbiome-relevant signatures in sepsis.

Key implications

Clinicians should view copper homeostasis as a modifiable axis of sepsis care. Monitoring copper and the copper-to-zinc ratio may aid risk assessment. Therapies that target microbial copper resistance, or that fine-tune host copper delivery, could improve pathogen control while limiting tissue damage. Copper ionophores and copper-mimetic nanoenzymes merit cautious evaluation as adjuncts, paired with strategies that protect the gut barrier to reduce dysbiosis and bacterial translocation. Any copper-based approach must balance antimicrobial gain against the risk of excess oxidative stress and cell death.