Abstract
For all microorganisms, acquisition of metal ions is essential for survival in the environment or in their infected host. Metal ions are required in many biological processes as components of metalloproteins and serve as cofactors or structural elements for enzymes. However, it is critical for bacteria to ensure that metal uptake and availability is in accordance with physiological needs, as an imbalance in bacterial metal homeostasis is deleterious. Indeed, host defense strategies against infection either consist of metal starvation by sequestration or toxicity by the highly concentrated release of metals. To overcome these host strategies, bacteria employ a variety of metal uptake and export systems and finely regulate metal homeostasis by numerous transcriptional regulators, allowing them to adapt to changing environmental conditions. As a consequence, iron, zinc, manganese, and copper uptake systems significantly contribute to the virulence of many pathogenic bacteria. However, during the course of our experiments on the role of iron and manganese transporters in extraintestinal Escherichia coli (ExPEC) virulence, we observed that depending on the strain tested, the importance of tested systems in virulence may be different. This could be due to the different set of systems present in these strains, but literature also suggests that as each pathogen must adapt to the particular microenvironment of its site of infection, the role of each acquisition system in virulence can differ from a particular strain to another. In this review, we present the systems involved in metal transport by Enterobacteria and the main regulators responsible for their controlled expression. We also discuss the relative role of these systems depending on the pathogen and the tissues they infect.
Highlights
Metal ions such as iron, copper, zinc, and manganese, are involved in many crucial biological processes and are necessary for the survival of all living organisms
When intracellular metal concentration increases, these regulators are activated and repress metal uptake, and other metal-bound regulators, such as ZntR, and Two-component regulatory systems (TCRS) activate efflux systems expression. This regulation www.frontiersin.org allows to obtain sufficient nutrient for biological functions when metal is scarce, and to limit toxicity in the cell in the presence of high concentrations of metal. This system is organized in a highly sophisticated network, as one transporter can be regulated by its own regulator and other sensors responding to metal availability and environmental signals such as oxidative stress, pH or oxygen
Fur and MntR have higher affinities for their cognate metals (10−6 M for iron and 10−5 M for manganese, respectively), corresponding to the intracellular concentrations of these metals. This suggests that more free iron and manganese are available in the cell for other weaker metal-binding proteins, as free zinc and copper concentrations are restricting by this regulation mechanism
Summary
Metal ions such as iron, copper, zinc, and manganese, are involved in many crucial biological processes and are necessary for the survival of all living organisms. The S. marcescens SfuABC, the K. pneumoniae KfuABC, the E. coli and Cronobacter sp EitABC and the Y. pestis YfuABC and YiuABC systems transport ferric iron bound to small chelators across the cytoplasmic membrane (Angerer et al, 1990; Gong et al, 2001; Ma et al, 2005; Johnson et al, 2006; Kirillina et al, 2006; Grim et al, 2012) This redundancy in siderophore-mediated iron acquisition systems suggests that their fundamental role lies in adaptation to different iron-limited niches in which bacteria are competing with other microorganisms in the environment or with host proteins for iron acquisition (Valdebenito et al, 2006). The iron uptake transporter efeUOB is repressed at high pH by dephosphorylated CpxR in response
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