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 Escherichia coli in a cultured macrophage cell line. In this investigation, we expanded on these studies by generating Atp7aLysMcre mice, in which the Atp7a gene was specifically deleted in cells of the myeloid lineage, including macrophages. Primary macrophages isolated from Atp7aLysMcre mice exhibit decreased
copper transport into phagosomal compartments and a reduced ability to kill Salmonella enterica serovar Typhimurium compared to that of macrophages isolated from wild-type mice. The Atp7aLysMcre mice were also more susceptible to systemic
infection by S Typhimurium than wild-type mice. Deletion of the S Typhimurium
copper exporters, CopA and GolT, was found to decrease
infection in wild-type mice but not in the Atp7aLysMcre mice. These studies suggest that ATP7A-dependent
copper transport into the phagosome mediates host defense against S 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.