TY - JOUR
T1 - Host and pathogen copper-transporting P-type ATPases function antagonistically during Salmonella infection
AU - Ladomersky, Erik
AU - Khan, Aslam
AU - Shanbhag, Vinit
AU - Cavet, Jennifer S.
AU - Chan, Jefferson
AU - Weisman, Gary A.
AU - Petris, Michael J.
N1 - Funding Information:
We thank members of our laboratories for helpful comments throughout this project. We thank the members of Chris Chang laboratory (University California, Berkeley) for providing the CF4 copper probe. This work was supported by grants from the National Institutes of Health (DK093386 and GM79465).
Publisher Copyright:
© 2017 American Society for Microbiology.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - 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.
AB - 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.
KW - ATP7A copper transporter
KW - Bacterial copper tolerance
KW - Bacterial infection
KW - Copper toxicity
KW - Host-pathogen interactions
KW - Immunology and infection
KW - Macrophages
KW - Nutritional immunity
KW - Salmonella Typhimurium
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U2 - 10.1128/IAI.00351-17
DO - 10.1128/IAI.00351-17
M3 - Article
C2 - 28652309
AN - SCOPUS:85027535328
VL - 85
JO - Infection and Immunity
JF - Infection and Immunity
SN - 0019-9567
IS - 9
M1 - e00351-17
ER -