title: Salmonella employs multiple mechanisms to subvert the TLR-inducible zinc-mediated antimicrobial response of human macrophages.
abstract: We aimed to characterize antimicrobial zinc trafficking within macrophages and to determine whether the professional intramacrophage pathogen Salmonella enterica serovar Typhimurium (S Typhimurium) subverts this pathway. Using both Escherichia coli and S Typhimurium, we show that TLR signaling promotes the accumulation of vesicular zinc within primary human macrophages. Vesicular zinc is delivered to E. coli to promote microbial clearance, whereas S. Typhimurium evades this response via Salmonella pathogenicity island (SPI)-1. Even in the absence of SPI-1 and the zinc exporter ZntA, S Typhimurium resists the innate immune zinc stress response, implying the existence of additional host subversion mechanisms. We also demonstrate the combinatorial antimicrobial effects of zinc and copper, a pathway that S. Typhimurium again evades. Our use of complementary tools and approaches, including confocal microscopy, direct assessment of intramacrophage bacterial zinc stress responses, specific E. coli and S Typhimurium mutants, and inductively coupled plasma mass spectroscopy, has enabled carefully controlled characterization of this novel innate immune antimicrobial pathway. In summary, our study provides new insights at the cellular level into the well-documented effects of zinc in promoting host defense against infectious disease, as well as the complex host subversion strategies employed by S Typhimurium to combat this pathway.-Kapetanovic, R., Bokil, N. J., Achard, M. E. S., Ong, C.-L. Y., Peters, K. M., Stocks, C. J., Phan, M.-D., Monteleone, M., Schroder, K., Irvine, K. M., Saunders, B. M., Walker, M. J., Stacey, K. J., McEwan, A. G., Schembri, M. A., Sweet, M. J. Salmonella employs multiple mechanisms to subvert the TLR-inducible zinc-mediated antimicrobial response of human macrophages.
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Australia; IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Ronan
authors.initials: R
authors.lastname: Kapetanovic
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Australia; IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Bokil
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Maud E S
authors.initials: ME
authors.lastname: Achard
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Cheryl-Lynn Y
authors.initials: CL
authors.lastname: Ong
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Kate M
authors.initials: KM
authors.lastname: Peters
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Australia; IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Claudia J
authors.initials: CJ
authors.lastname: Stocks
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Minh-Duy
authors.initials: MD
authors.lastname: Phan
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Australia; IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Mercedes
authors.initials: M
authors.lastname: Monteleone
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Australia; IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
authors.affiliation: IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Australia; School of Medicine, The University of Queensland, Woolloongabba, Australia; and.
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Irvine
authors.affiliation: School of Life Sciences, University of Technology, Sydney, Australia.
authors.forename: Bernadette M
authors.initials: BM
authors.lastname: Saunders
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walker
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Katryn J
authors.initials: KJ
authors.lastname: Stacey
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Alastair G
authors.initials: AG
authors.lastname: McEwan
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia;
authors.forename: Mark A
authors.initials: MA
authors.lastname: Schembri
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Australia; IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia; m.sweet@imb.uq.edu.au.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003300:Copper; D022162:Cytoplasmic Vesicles / Q000737:chemistry / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D012329:RNA, Bacterial / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012475:Salmonella / Q000502:physiology*; D012486:Salmonella typhimurium / Q000502:physiology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D012329:RNA, Bacterial; D012333:RNA, Messenger; C419942:Spi1 protein, Salmonella; D051193:Toll-Like Receptors; D003300:Copper; D015032:Zinc
keywords: bacterial pathogens; innate immunity; metal ions; trafficking pathways