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.