Re-Zincing the macrophage antimicrobial response to Salmonella typhimurium. — ASN Events
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  3. Re-Zincing the macrophage antimicrobial response to Salmonella typhimurium.

Re-Zincing the macrophage antimicrobial response to Salmonella typhimurium. (#277)

Ronan Kapetanovic 1 , Nilesh J Bokil 1 , Maud ES Achard 2 , Kate Peters 2 , Minh Duy Phan 2 , Han Rong Foo 1 , Nick A Hamilton 1 , Kate Schroder 1 , Katharine M Irvine 3 , Bernadette M Saunders 4 , Kate J Stacey 2 , Alastair G McEwan 2 , Mark A Schembri 2 , Matthew J Sweet 1
  1. Institute for Molecular Bioscience, Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland , St Lucia, QLD, Australia
  2. School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, St Lucia, QLD, Australia
  3. School of Medicine, The University of Queensland, Wooloongabba, QLD, Australia
  4. Mycobacterial Research Program, Centenary Institute, Locked Bag No. 6, Sydney, NSW, Australia

Zinc deficiency predisposes to infectious diseases and zinc supplementation is associated with improved outcomes in severe diarrheal disease. Cytokines, including TNF and IL-6, released during inflammatory events induce an acute redistribution of the zinc, leading to plasma zinc depletion. Here we investigated potential antimicrobial effects of zinc in human macrophages.

We show Toll-like Receptor (TLR) signalling promotes the delayed accumulation of vesicular zinc within primary human macrophages. Treatment of macrophages with exogenous zinc does not alter LPS-dependent TNF and IL-6 production but increased the intracellular zinc pool. After infection, the vesicular zinc is delivered to non-pathogenic Escherichia coli (E. coli) strain MG1655 for microbial clearance. In contrast, Salmonella enterica serovar Typhimurium (S. Typhimurium) evades this response via a mechanism dependent upon Salmonella pathogenicity island-1 (SPI-1); a SPI-1 mutant, but not wild type S. Typhimurium, co-localized with zinc-containing vesicles. The antimicrobial effect of exogenous zinc was more pronounced with E. coli than with S. Typhimurium, suggesting that S. Typhimurium may employ additional mechanisms to evade zinc-mediated antimicrobial responses. Indeed, intramacrophage S. Typhimurium upregulated expression of the zinc exporter zntA, which effluxes zinc when concentrations reach cytotoxic levels. The SPI1 mutant displayed prolonged up-regulation of zntA within macrophages, consistent with its sustained exposure to zinc in this environment. Interestingly, Salmonella zntA mRNA is upregulated by both zinc and copper, and both metals ions colocalise in vesicles in TLR-activated macrophages. Furthermore, copper and zinc synergized to reduce bacterial growth of the Salmonella zntA mutant.

Our data thus suggest that S. Typhimurium employs multiple mechanisms of zinc evasion including SPI-1-dependent subversion of zinc delivery, upregulation of zntA and an additional yet to be characterized mechanism. In total, our findings identify roles for zinc and zinc trafficking in human macrophage antimicrobial pathways against Gram-negative bacteria, and provide insights into host subversion.