A critical response of the innate immune system to microbial infection is the ingestion, destruction and clearance of pathogens by activated phagocytic cells. Within their phagosomal compartments, macrophages generate an environment that is hostile to microbes via the production of reactive oxygen and nitrogen species, the elaboration of proteases, acidification of the phagosomal lumen and the export of iron.1,2 Unlike iron, copper (Cu) is not essential for many pathogens, although it is an essential trace element for mammals. In fact, Cu has been used for over a century as a microbiocidal agent for the elimination of human and plant pathogens.3 Moreover, Cu is critical for normal innate immune cell function and Cu deficiency in mammals renders the host susceptible to microbial pathogens. It is well documented that Cu levels rise dramatically in the serum of mammals during infection/inflammation and Cu accumulates at sites of inflammation, underscoring a specialized role for Cu in innate immunity.4,5 Consistent with a microbiocidal role for Cu in macrophages, phagosomal Cu concentrations rise dramatically in activated macrophages in parallel with increased expression of the Ctrl plasma membrane Cu importer and the Atp7A Cu pump on the phagosomal membrane.6, 7 Moreover, studies in both prokaryotic and fungal pathogens demonstrate the requirement for the Cu homeostasis machinery in resistance to macrophage killing.7, 8 Together, these studies provide compelling evidence for a critical role of Cu in microbiocidal activity of the host, which is countered by the Cu homeostasis machinery of invading bacterial and fungal pathogens.
Biocidal properties of Cu have been documented since ancient Egyptians used it for water and wound sterilization in 2400 B.C.9 The Bordeaux mixture of copper sulfate and lime has been used since 1880 as a fungicide for grapes and other plants,3 while metallic Cu surfaces, which likely release Cu ions upon bacterial contact, may reduce contamination in hospitals.10-12 Metallic Cu, Cu salts, and Cu compounds continue to be used to control bacterial, fungal, and algal growth in agricultural and healthcare settings where microbes exist in the environment.3 The environment of pathogenic microbes, however, is ultimately the infected host, and while Cu and its complexes have been used for so long as environmental antimicrobials, no approach to date has been effective at using Cu to fight infection in a mammalian host. A challenge in this area is to discover ways to deliver or reallocate Cu selectively to the site of infection or inflammation.4 