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Review
. 2012 Apr 20;287(17):13549-55.
doi: 10.1074/jbc.R111.316406. Epub 2012 Mar 2.

Copper homeostasis at the host-pathogen interface

Victoria Hodgkinson  1 , Michael J Petris
Affiliations
Review

Copper homeostasis at the host-pathogen interface

Victoria Hodgkinson et al. J Biol Chem. .

Abstract

The trace element copper is indispensable for all aerobic life forms. Its ability to cycle between two oxidation states, Cu(1+) and Cu(2+), has been harnessed by a wide array of metalloenzymes that catalyze electron transfer reactions. The metabolic needs for copper are sustained by a complex series of transporters and carrier proteins that regulate its intracellular accumulation and distribution in both pathogenic microbes and their animal hosts. However, copper is also potentially toxic due in part to its ability to generate reactive oxygen species. Recent studies suggest that the macrophage phagosome accumulates copper during bacterial infection, which may constitute an important mechanism of killing. Bacterial countermeasures include the up-regulation of copper export and detoxification genes during infection, which studies suggest are important determinants of virulence. In this minireview, we summarize recent developments that suggest an emerging role for copper as an unexpected component in determining the outcome of host-pathogen interactions.

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Figures

FIGURE 1.
FIGURE 1.
Model of copper-mediated bacterial killing by the activated macrophage. Inflammatory agents (e.g. lipopolysaccharide) stimulate copper uptake by inducing the expression of the CTR1 copper importer at the plasma membrane. Cytoplasmic copper is delivered via the ATOX copper chaperone to the ATP7A copper pump, which undergoes trafficking to the phagolysosomal compartment, into which it loads copper. The NADPH oxidase (NOX) produces superoxide, which spontaneously generates hydrogen peroxide, the bactericidal potency of which is augmented by conversion to the hydroxyl radical via Cu(I)-catalyzed Fenton chemistry. Cu(I) may also function as a bactericidal agent by disruption of Fe-S clusters. Copper homeostasis proteins of S. typhimurium and M. tuberculosis are shown. Those in color are known to contribute to survival within cultured macrophages or in animal models of infection as described in the text.
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