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

Abstract

Zinc (Zn) and copper (Cu) are essential for optimal innate immune function, and nutritional deficiency in either metal leads to increased susceptibility to bacterial infection. Recently, the decreased survival of bacterial pathogens with impaired Cu and/or Zn detoxification systems in phagocytes and animal models of infection has been reported. Consequently, a model has emerged in which the host utilizes Cu and/or Zn intoxication to reduce the intracellular survival of pathogens. This review describes and assesses the potential role for Cu and Zn intoxication in innate immune function and their direct bactericidal function.Six first row d-block metal ions, manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), and zinc (Zn), are essential micronutrients in living organisms. Investigations and discussions of the roles of these trace metals in biology often relate to their acquisition, storage, and incorporation into enzymes. However, conditions where these metal ions are present in excess or are found in the wrong location, resulting in toxicity, have also been described. Thus, there are also systems that sequester, export, and detoxify excess trace metal ions. Today, the concept of trace metal homeostasis, in which various cellular actions maintain the fine balance between nutrition and toxicity, is well developed.Recently, the concept of "nutritional immunity" has emerged in the context of host defense against pathogens. This envisages a role for mechanisms that protect the host from invading pathogens by restricting their ability to acquire key transition metal ions. One example involves lipocalin, which binds siderophores and thereby prevents Fe acquisition by bacterial pathogens (1). Another is calprotectin, which restricts acquisition of Zn or Mn (2). However, what if the host was able to harness the toxic properties of transition metal ions and use them as bactericides? This review explores the evidence for an antimicrobial role for Cu and Zn in the host defense against bacterial pathogens.

Nutrient deficiencies (Copper, Zinc, Iron, Magnesium) among children with SIRS/sepsis-a hospital based cross sectional study

“…11,6 Contrary to this Djoko KY et al in their study showed that copper levels were low in sepsis and deficient subjects had more morbidity due to infections and worse prognosis. 12 Serum zinc levels were low in majority of patients which was similar to studies done by Djoko KY et al, Wang G et al 12,6 This evidence is further supported by a study by, Srinivasan MG in which subjects supplemented with zinc had less infections. 13 In contrary to this study done by Duncan A et al in their study demonstrated that zinc supplementation has no role in preventing infections.…”

“…Contrary to this, in studies done by Wang G et al, Djoko KY et al, Bresnahan K serum iron levels were low in children with sepsis. 6,12,15 Serum magnesium levels of children were low in greater proportion proportion of children similar to study by Cojocaru IM et al were children with acute infections had low serum magnesium values but there was no correlation found with severity of the disease. Similar observations were seen in study by Tam M et al 16,17 Children with prolonged duration of illness prior to diagnosis had higher proportion of deficiencies of copper, zinc and iron, with median serum level significant for magnesium which can be due to severity of the disease or more sequestration of these nutrients for immune function as postulated by Visser J et al 5 Proportion of children with deficiencies of copper, zinc, magnesium increased and median serum zinc value was significantly low in children with prolonged hospital stay.…”

Compartment and signal-specific codependence in the transcriptional control of Salmonella periplasmic copper homeostasis

“…The essential as well as toxic nature of copper makes its active handling a vital skill for most organisms (6,11). Recently reported evidence indicates that intracellular copper actively contributes to the host innate immune response against bacterial infections, and that pathogens have acquired specific traits to deal with this intoxicant (29)(30)(31).…”

Bacterial copper storage proteins

“…As mentioned in the introduction, and covered in previous Minireviews in this Series, the interplay between Cu homeostasis systems in a pathogen and host is emerging as important for virulence (30)(31)(32)(33)(34)91). Compared to nutritional immunity used to withhold other essential metal ions, hosts are thought to expose invading pathogens to Cu (32,33,91).…”

“…Compared to nutritional immunity used to withhold other essential metal ions, hosts are thought to expose invading pathogens to Cu (32,33,91). In mammalian hosts ATP7A pumps Cu into the phagolysosomal compartment and Cu homeostasis systems can protect the pathogen against this attack (30)(31)(32)(33)(91)(92)(93).…”