Host and pathogen copper-transporting P-type ATPases function antagonistically during Salmonella infection

Erik Ladomersky, Aslam Khan, Vinit Shanbhag, Jennifer S Cavet, Jefferson Chan, Gary A Weisman, Michael J Petris

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Abstract

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. Herein, we expand on these studies by generating Atp7a(LysMcre) mice in which the Atp7a gene was specifically deleted in cells of the myeloid lineage including macrophages. Primary macrophages isolated from Atp7a(LysMcre) mice exhibit decreased copper transport into phagosomal compartments and a reduced ability to kill Salmonella typhimurium compared to macrophages isolated from wild type mice. The Atp7a(LysMcre) mice are 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 Atp7a(LysMcre) 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.

Original languageEnglish
Pages (from-to)e00351-17
JournalInfection and immunity
Volume85
Early online date26 Jun 2017
DOIs
Publication statusPublished - 26 Jun 2017

Keywords

  • Journal Article

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