Copper microenvironments in the human body define patterns of copper adaptation in pathogenic bacteria

Abstract

Copper is an essential micronutrient for most organisms that is required as a cofactor for crucial copper-dependent enzymes encoded by both prokaryotes and eukaryotes. Evidence accumulated over several decades has shown that copper plays important roles in the function of the mammalian immune system. Copper accumulates at sites of infection, including the gastrointestinal and respiratory tracts and in blood and urine, and its antibacterial toxicity is directly leveraged by phagocytic cells to kill pathogens. Copper-deficient animals are more susceptible to infection, whereas those fed copper-rich diets are more resistant. As a result, copper resistance genes are important virulence factors for bacterial pathogens, enabling them to detoxify the copper insult while maintaining copper supply to their essential cuproenzymes. Here, we describe the accumulated evidence for the varied roles of copper in the mammalian response to infections, demonstrating that this metal has numerous direct and indirect effects on immune function. We further illustrate the multifaceted response of pathogenic bacteria to the elevated copper concentrations that they experience when invading the host, describing both conserved and species-specific adaptations to copper toxicity. Together, these observations demonstrate the roles of copper at the host–pathogen interface and illustrate why bacterial copper detoxification systems can be viable targets for the future development of novel antibiotic drug development programs.

Circulating levels of micronutrients and risk of infections: a Mendelian randomization study

“…Copper plays an essential role in innate and adaptive immunity: it regulates the function of T helper cells, B cells, neutrophils, natural killer cells, and macrophages; it accumulates at sites of inflammation, including the gastrointestinal and respiratory tract and in blood and urine, and is vital for interleukin 2 production and response [3,48]. Blood levels of copper have not previously been robustly linked to the risk of gastrointestinal infections in humans.…”

Copper/Zinc Ratio in Childhood and Adolescence: A Review

“…Cardiovascular diseases are the leading cause of death worldwide [ 53 ]. Although in 39 children with a diagnosis of congenital heart disease (CHD: 11 with cyanotic and 28 with acyanotic CHD), which is the most common birth defect (incidence of 1.9 to 9.3/1000), there were no significant differences in blood sample for Zn, Cu, and Zn/Cu ratio, the teeth–Cu level was considerably higher in the CHD group [ 28 ]. The most prominent CV risk factors in children and adolescents are overweight, arterial HTN, and alterations in lipid and glucose metabolism [ 54 ].…”

Unscrambling the Role of Redox-Active Biometals in Dopaminergic Neuronal Death and Promising Metal Chelation-Based Therapy for Parkinson’s Disease

“…Copper is a trace element that constitutes 70 parts per million of the Earth’s crust. However, it is an essential micronutrient found in small amounts in tissues and cells, with a high concentration in the kidney, liver, and brain [ 111 ].…”