Host and Pathogen Copper-Transporting P-Type ATPases Function Antagonistically during Salmonella Infection.

Copper is an essential yet potentially toxic trace element that is required by all aerobic organisms. A key regulator of copper homeostasis in mammalian cells is the copper-transporting P-type ATPase ATP7A, which mediates copper transport from the cytoplasm into the secretory pathway, as well as copper export across the plasma membrane. Previous studies have shown that ATP7A-dependent copper transport is required for killing phagocytosed in a cultured macrophage cell line. In this investigation, we expanded on these studies by generating mice, in which the gene was specifically deleted in cells of the myeloid lineage, including macrophages. Primary macrophages isolated from mice exhibit decreased copper transport into phagosomal compartments and a reduced ability to kill serovar Typhimurium compared to that of macrophages isolated from wild-type mice. The mice were also more susceptible to systemic infection by Typhimurium than wild-type mice. Deletion of the Typhimurium copper exporters, CopA and GolT, was found to decrease infection in wild-type mice but not in the mice. These studies suggest that ATP7A-dependent copper transport into the phagosome mediates host defense against Typhimurium, which is counteracted by copper export from the bacteria via CopA and GolT. These findings reveal unique and opposing functions for copper transporters of the host and pathogen during infection.