The Yin and Yang of copper during infection

Abstract

Copper is an essential micronutrient for both pathogens and the animal hosts they infect. However, copper can also be toxic in cells due to its redox properties and ability to disrupt active sites of metalloproteins, such as Fe-S enzymes. Through these toxic properties, copper is an effective antimicrobial agent and an emerging concept in innate immunity is that the animal host intentionally exploits copper toxicity in antimicrobial weaponry. In particular, macrophages can attack invading microbes with high copper and this metal is also elevated at sites of lung infection. In addition, copper levels in serum rise during infection with a wide array of pathogens. To defend against this toxic copper, the microbial intruder is equipped with a battery of copper detoxification defenses that promote survival in the host, including copper exporting ATPases and copper binding metallothioneins. However, it is important to remember that copper is also an essential nutrient for microbial pathogens and serves as important cofactor for enzymes such as cytochrome c oxidase for respiration, superoxide dismutase for anti-oxidant defense and multi-copper oxidases that act on metals and organic substrates. We therefore posit that the animal host can also thwart pathogen growth by limiting their copper nutrients, similar to the well-documented nutritional immunity effects for starving microbes of essential zinc, manganese and iron micronutrients. This review provides both sides of the copper story and evaluates how the host can exploit either copper-the-toxin or copper-the-nutrient in antimicrobial tactics at the host-pathogen battleground.

Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus

“…As Cu is an essential trace element for most living organisms, and can also be toxic to cells due to its redox properties, Cu is an effective antimicrobial agent and also used by mammalian host cells as defense mechanisms [12]. In the phagolysosome, where macrophages compartmentalize microbial invaders, reactive oxygen intermediates (ROIs), reactive nitrogen intermediates (RNIs) and low pH conditions are generated to kill pathogens.…”

“…In the phagolysosome, where macrophages compartmentalize microbial invaders, reactive oxygen intermediates (ROIs), reactive nitrogen intermediates (RNIs) and low pH conditions are generated to kill pathogens. To attack the invading microbes with excess Cu at the infection site of lung, macrophages elevated the Cu level by inducing expression of both ATP7A and Ctr1 [7,12]. A significant induction of Ctr1 was found in A. fumigatus challenged macrophages, indicating that Cu is mobilized against the fungal invader [15].…”

“…The anti-microbial properties of Cu are also used by mammalian host cells as defense mechanisms. For example, Cu plays an important role in innate immune defense to microbial infection in mammals [8,11,12]. Previous studies demonstrated that, upon activation by a pathogen, macrophages elevate the expression levels of high-affinity Cu + importer Ctr1 and P-type Cu ATPase, ATP7A, leading to increased levels of Cu in the phagosome of IFN-γ stimulated macrophages [13,14].…”

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

“…C. albicans and other pathogenic microbes must acquire these metals from the host, and as part of the innate immune response, the host attempts to limit metal availability through a process known as nutritional immunity (2)(3)(4)(5). However, transition metals are also potentially toxic to microbes, and with Zn and Cu there is increasing evidence that the host also exploits toxic levels of these metals in its antimicrobial weaponry (2,6). In the case of C. albicans, host Cu appears dynamic when the fungus invades the kidney in a mouse model of disseminated candidiasis.…”

“…This site has been termed Zn selective based on its picomolar to nanomolar affinity for this metal, with much weaker affinity for Mn, Fe, and Ni (28,30,31,34,35). As mentioned above, Cu is another important micronutrient for microbes, particularly eukaryotic microbes (2). To date, CP binding to Cu has not been reported, although fluorescence studies suggest that Cu can induce conformational changes in CP (36), and other S100 proteins, including S100B, S100A12, and S100A13, have been shown to bind this metal ion (37)(38)(39)(40), raising the possibility of a role for CP in Cu sequestration.…”