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

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish (US)
Article numbere00351-17
JournalInfection and immunity
Volume85
Issue number9
DOIs
StatePublished - Sep 1 2017

Keywords

  • ATP7A copper transporter
  • Bacterial copper tolerance
  • Bacterial infection
  • Copper toxicity
  • Host-pathogen interactions
  • Immunology and infection
  • Macrophages
  • Nutritional immunity
  • Salmonella Typhimurium

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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  • Cite this

    Ladomersky, E., Khan, A., Shanbhag, V., Cavet, J. S., Chan, J., Weisman, G. A., & Petris, M. J. (2017). Host and pathogen copper-transporting P-type ATPases function antagonistically during Salmonella infection. Infection and immunity, 85(9), [e00351-17]. https://doi.org/10.1128/IAI.00351-17