Abstract
ABSTRACTZinc sequestration by macrophages is considered a crucial host defense strategy against infection by the intracellular bacterium Salmonella enterica serovar Typhimurium. However, the underlying mechanisms remain elusive. In this study, we found that zinc favors pathogen survival within macrophages. Salmonella-hosting macrophages contained higher free zinc levels than did uninfected macrophages and cells that successfully eliminated bacteria, which was paralleled by the impaired production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in bacterium-harboring cells. A profound, zinc-mediated inhibition of NF-κB p65 transcriptional activity affecting the expression of the ROS- and RNS-forming enzymes phos47 and inducible nitric oxide synthase (iNOS) provided a mechanistic explanation for this phenomenon. Macrophages responded to infection by enhancing the expression of zinc-scavenging metallothioneins 1 and 2, whose genetic deletion caused increased free zinc levels, reduced ROS and RNS production, and increased the survival of Salmonella. Our data suggest that Salmonella invasion of macrophages results in a bacterium-driven increase in the intracellular zinc level, which weakens antimicrobial defense and the ability of macrophages to eradicate the pathogen. Thus, limitation of cytoplasmic zinc levels may help to control infection by intracellular bacteria.
Highlights
We found that Salmonella induces the accumulation of protein-unbound zinc in infected macrophages to impair fully fledged Nuclear factor kappa B (NF-B) activation, which is essential for the transcriptional induction of NADPH oxidase and inducible nitric oxide synthase (iNOS)
We utilized the RAW264.7 macrophage cell line and the intracellular bacterium Salmonella Typhimurium to study the impact of cellular zinc availability on host-pathogen interactions
We observed significantly reduced reactive oxygen species (ROS) production (Fig. 5C) and iNOS mRNA (Fig. 5D) and iNOS protein (Fig. 5E) expression levels in Salmonella-hosting macrophages compared to bacterium-negative cells
Summary
Zinc sequestration by macrophages is considered a crucial host defense strategy against infection by the intracellular bacterium Salmonella enterica serovar Typhimurium. Macrophages, which constitute the first line of antimicrobial defense, are equipped with a broad repertoire of mechanisms to clear intracellular bacteria [1, 2] One such strategy is to limit the availability of nutrients important for microbial growth, such as iron, copper, manganese, or zinc [3,4,5,6]. Whereas the role of iron in the host-pathogen interaction in infection by intracellular bacteria such as Salmonella enterica serovar Typhimurium or mycobacteria has been extensively studied [7,8,9], far less is known about the role of zinc in this setting.
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