Salmonella Utilizes Zinc To Subvert Antimicrobial Host Defense of Macrophages via Modulation of NF-κB Signaling

Zinc sequestration by macrophages is considered a crucial host defense strategy against infection with the intracellular bacterium Salmonella Typhimurium. However, the underlying mechanisms remain elusive. In this study we found zinc to favor pathogen survival within macrophages. Salmonella-hosting macrophages contained higher free zinc levels than uninfected macrophages and cells that successfully eliminated bacteria, which was paralleled by impaired production of reactive oxygen (ROS) and nitrogen (RNS) species in bacteria-harboring cells. A profound, zinc-mediated inhibition of NF-κB p65 transcriptional activity affecting expression of the ROS- and RNS-forming enzymes phos47 and iNOS provided a mechanistic explanation for this phenomenon. Macrophages responded to infection by enhanced expression of zinc scavenging methallothioneins-1 and 2, whose genetic deletion caused a rise of free zinc levels, reduced ROS and RNS production and increased survival of Salmonella Our data suggest that Salmonella invasion of macrophages results in a bacteria-driven rise of intracellular zinc levels which weakens anti-microbial defense and the ability of macrophages to eradicate the pathogen. Thus, limitation of cytoplasmic zinc levels may help to control infection with intracellular bacteria.