Fig. 2

Host Bactericidal Immune Defence Facilitated by Trace Metals. Metals play a pivotal role in contributing to the host immune response during bacterial infection. They can be used by immune cells to either mediate metal toxicity to rapidly kill the bacteria or be sequestered away in order to deprive the bacteria of essential metals in order to limit bacterial growth and replication. Whether the metals are sequestered or used to facilitate toxicity mechanisms is highly dependent on the nature of the bacterial infection. (1) Intracellular bacteria are mainly located within the phagosome of their host cell. Here they release siderophores allowing them to scavenge iron within the cell. In response, the host limits bacterial iron supply by exporting iron out of the infected phagosome via the NRAMP1 transporter. Furthermore, the host employs toxicity mechanisms by which both zinc and copper are pumped into the infected phagosome via their respective transporters in order to limit bacterial growth and replication. (2) Extracellular bacteria produce numerous different proteins to mediate metal acquisition from the host. The majority produce siderophores, which vary between bacterial species. However, they all function to supply the bacteria with an adequate amount of iron. The host also employs mechanisms to limit the amount of metals available to the bacteria in the extracellular space. Iron is sequestered by the upregulation of hepcidin resulting in the degradation of FPN which reduces the amount of iron exported from the cell. Furthermore, the iron importer DMT1 is also upregulated in both macrophages and neutrophils. Several metal binding proteins have also been shown to be produced mainly by neutrophils to bind extracellular metals. Lipocalin2, produced in secondary granules of neutrophils, binds bacterial siderophores and shuttles them away from the bacteria to the host cell. S100 proteins such as Calprotectin that binds zinc and manganese, and Calgranulin C binding zinc and copper also sequester these metals out of the extracellular space