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Chapter 5 : Regulation of Virulence by Iron in Gram-Positive Bacteria

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Abstract:

This chapter discusses the mechanisms by which vertebrates sequester iron from invading pathogens and the response of pathogens to this sequestration. It provides examples of iron-regulated virulence determinants in several clinically important gram-positive bacteria. Iron is crucial to the activity of ribonucleotide reductase, nitrogenase, peroxidase, catalase, and succinic dehydrogenase, and it is therefore required for the vital functions of respiration and several metabolic pathways. During infection, pathogens must rely on their host as the sole source of nutrient iron. Diseases in iron metabolism impact susceptibility to infection, exemplified by an increased frequency of infections caused by , , and in patients with high iron levels. Transcriptional regulation of bacterial genes in response to iron occurs through the activity of metal-dependent regulators. is the causative agent of diphtheria, a contagious upper respiratory tract infection that has been largely eradicated in the last century due to worldwide utilization of the diphtheria vaccines. The iron-containing tetrapyrrole heme is the preferentially bound iron source of . Iron-dependent virulence gene expression in involves a complex regulatory network comprised of Fur and the two-component systems Agr and Sae, which regulate quorum sensing and secreted virulence factors, respectively.

Citation: Farrand A, Skaar E. 2013. Regulation of Virulence by Iron in Gram-Positive Bacteria, p 79-105. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch5
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Figure 1

Nutritional immunity: host-mediated iron sequestration and theft of iron by pathogens. Vertebrate hosts employ several mechanisms to withhold nutrient iron from invading pathogens during infection. Most iron is located intracellularly, complexed to hemoglobin in erythrocytes or stored within ferritin inside host cells. Lactoferrin (Lf) and transferrin (Tf) transport iron to cells throughout the body and are internalized through the transferrin receptor (Tf R) on host cells. Invading pathogens respond by producing dedicated systems to steal host iron. In some pathogens, hemoglobin is released from erythrocytes following lysis of the cells by bacterial hemolysins and can be imported through the bacterial membrane via heme transporters (HT) or bound by host haptoglobin (Hap) or hemopexin (HP). Host iron can be obtained by the pathogen through direct import via iron transporters (Fe T) or through iron-chelating siderophores (SP), which are secreted from the pathogen to scavenge available extracellular iron. In response, the host produces siderocalin (SC), which can bind some siderophores and prevent them from being utilized by the pathogen. doi:10.1128/9781555818524.ch5f5

Citation: Farrand A, Skaar E. 2013. Regulation of Virulence by Iron in Gram-Positive Bacteria, p 79-105. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch5
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Figure 2

The Fenton reaction. Ferrous iron catalyzes the reaction, in which hydrogen peroxide is broken down into a hydroxyl radical and hydroxyl anion and the metal is oxidized to ferric iron. Hydroxyl radicals are a form of oxidative stress that damages DNA, proteins, and lipids within a cell. doi:10.1128/9781555818524.ch5f2

Citation: Farrand A, Skaar E. 2013. Regulation of Virulence by Iron in Gram-Positive Bacteria, p 79-105. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch5
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Figure 3

Mechanism of iron-dependent regulation in gram-positive bacteria. The metalloregulators Fur and DtxR regulate expression of a subset of genes in response to the availability of iron. Under iron-rich conditions, the metal binds to the regulator and activates it, allowing the protein to dimerize and bind to iron boxes in the promoter regions of genes within its regulon. Dimers bind to both strands of the double helix and prevent transcription. When iron levels are low, the regulators are not iron bound and no longer remain bound to the consensus sequence, and transcription is allowed to proceed. doi:10.1128/9781555818524.ch5f3

Citation: Farrand A, Skaar E. 2013. Regulation of Virulence by Iron in Gram-Positive Bacteria, p 79-105. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch5
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Figure 4

Structural characteristics of gram-positive metalloregulators. The crystal structures of the two primary iron-dependent metalloregulators in gram-positive bacteria are shown in ribbon diagram ( ). The ferric uptake regulator, Fur, and diphtheria toxin regulator, DtxR, share very little sequence homology but contain similar tertiary structures. The DNA binding domain of both regulators, shown in red, interacts with the consensus iron box sequence in the promoter of Fur- or DtxR-regulated genes. The dimerization domain, shown in blue, allows for two regulator subunits to interact with each other and the DNA strand. The dimerization domain also contains two metal binding sites, shown in green and orange, which bind iron or manganese to activate the regulator and promote DNA binding. DtxR also contains a unique SH3-like domain, shown in yellow, which is attached to the dimerization domain by a flexible linker and is believed to stabilize the molecule while it is bound to DNA. doi:10.1128/9781555818524.ch5f4

Citation: Farrand A, Skaar E. 2013. Regulation of Virulence by Iron in Gram-Positive Bacteria, p 79-105. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch5
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