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Iron Acquisition Strategies of Bacterial Pathogens

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  • Authors: Jessica R. Sheldon1, Holly A. Laakso2, David E. Heinrichs3
  • Editors: Indira T. Kudva4, Nancy A. Cornick5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6A 5C1; 2: Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6A 5C1; 3: Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6A 5C1; 4: National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, IA; 5: Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA
  • Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0010-2015
  • Received 03 March 2015 Accepted 22 April 2015 Published 18 March 2016
  • David E. Heinrichs, deh@uwo.ca
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  • Abstract:

    Iron is an essential micronutrient for both microbes and humans alike. For well over half a century we have known that this element, in particular, plays a pivotal role in health and disease and, most especially, in shaping host-pathogen interactions. Intracellular iron concentrations serve as a critical signal in regulating the expression not only of high-affinity iron acquisition systems in bacteria, but also of toxins and other noted virulence factors produced by some major human pathogens. While we now are aware of many strategies that the host has devised to sequester iron from invading microbes, there are as many if not more sophisticated mechanisms by which successful pathogens overcome nutritional immunity imposed by the host. This review discusses some of the essential components of iron sequestration and scavenging mechanisms of the host, as well as representative Gram-negative and Gram-positive pathogens, and highlights recent advances in the field. Last, we address how the iron acquisition strategies of pathogenic bacteria may be exploited for the development of novel prophylactics or antimicrobials.

  • Citation: Sheldon J, Laakso H, Heinrichs D. 2016. Iron Acquisition Strategies of Bacterial Pathogens. Microbiol Spectrum 4(2):VMBF-0010-2015. doi:10.1128/microbiolspec.VMBF-0010-2015.

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/content/journal/microbiolspec/10.1128/microbiolspec.VMBF-0010-2015
2016-03-18
2017-09-25

Abstract:

Iron is an essential micronutrient for both microbes and humans alike. For well over half a century we have known that this element, in particular, plays a pivotal role in health and disease and, most especially, in shaping host-pathogen interactions. Intracellular iron concentrations serve as a critical signal in regulating the expression not only of high-affinity iron acquisition systems in bacteria, but also of toxins and other noted virulence factors produced by some major human pathogens. While we now are aware of many strategies that the host has devised to sequester iron from invading microbes, there are as many if not more sophisticated mechanisms by which successful pathogens overcome nutritional immunity imposed by the host. This review discusses some of the essential components of iron sequestration and scavenging mechanisms of the host, as well as representative Gram-negative and Gram-positive pathogens, and highlights recent advances in the field. Last, we address how the iron acquisition strategies of pathogenic bacteria may be exploited for the development of novel prophylactics or antimicrobials.

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Figures

Image of FIGURE 1
FIGURE 1

The host versus pathogen battle for iron. Cartoon representation of the various strategies used by the host to sequester iron from invading pathogens and the counter strategies used by pathogens to obtain host iron. On mucosal surfaces, lactoferrin sequesters iron, yet bacteria can obtain iron from lactoferrin by secreting siderophores (i to iii), directly binding lactoferrin (iv), or by secreting reductases (pink pill) that reduce iron from FeIII to FeII, releasing it from lactoferrin (v to viii). Bacteria can obtain iron bound to heme by secreting hemolysins which release intracellular hemoglobin and heme into the blood. While the host uses hemoglobin- and heme-scavenging proteins to sequester these iron sources, bacteria have mechanisms to counter these systems (1 to 12). Macrophages move iron from the phagosome and the cell using natural resistance macrophage protein 1 and ferroportin, respectively, to keep iron from intracellular pathogens. In response to binding by the iron homeostasis hormone hepcidin, membrane-bound ferroportin is degraded, thus withholding iron in intracellular compartments. FeII that is secreted is rapidly oxidized by ceruloplasmin (Cp), and the FeIII is quickly picked up by transferrin (a, b). Transferrin-bound iron is scavenged by bacteria using transferrin-binding proteins (c) or through secretion of siderophores (d to f). Bacteria can also obtain iron using the mammalian siderophore 2,5-DHBA (g). Neutrophils secrete NGAL (also known as siderocalin, lipocalin 2, or 24p3) (I) which serves to capture some bacterial siderophores (II, III). Some bacteria synthesize and secrete stealth siderophores which are not bound by NGAL and can remove transferrin-bound iron even in the presence of NGAL (IV to VI). Lf, lactoferrin; Tf, transferrin; sid, siderophore; Hp, haptoglobin; Hx, hemopexin; Hb, hemoglobin; Hm, heme; Cp, ceruloplasmin.

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0010-2015
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Image of FIGURE 2
FIGURE 2

Model of iron uptake mechanisms in Gram-negative and Gram-positive bacteria. Diagrams depicting the envelope proteins required for the uptake of iron, or iron scavenged from siderophores, heme, or transferrin. This is a composite diagram and represents mechanisms used by many pathogenic bacteria, as described in the text. OM, outer membrane; PG, peptidoglycan; CM, cytoplasmic membrane; sid, FeIII-siderophore; Hm, heme; Tf, transferrin; OMP, outer membrane porin; HO, heme oxygenase; Hb, hemoglobin; Hp, haptoglobin. Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Microbiology ( 274 ), copyright 2012.

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0010-2015
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Image of FIGURE 3
FIGURE 3

Model of TonB-dependent transport in Gram-negative bacteria. An iron-siderophore complex (blue hexagon) entering through a TonB-dependent transporter (TBDT) in the outer membrane (OM). Although the transport of an iron siderophore complex is shown here, iron, or other iron complexes, use similar uptake mechanisms (e.g., FeIII, heme) (see Fig. 1 ). Movement through the TBDT requires an interaction of the TonB box (located near the N-terminus of the TBDT sequence) with the TonB protein, with the energy for conformational changes provided by the proton motive force captured by the ExbB and ExbD proteins. Once in the periplasm, the iron-loaded siderophore complex is recognized by a substrate-binding protein which delivers the complex to an ABC transporter in the cytoplasmic membrane (CM). Depending on the particular system, iron is released from the siderophore in the cytoplasm by either destruction of the siderophore or reduction on the metal (as shown). Intracellular iron, via Fur, negatively regulates transcription of genes encoding high-affinity iron acquisition systems. In some TBDTs, an N-terminal extension is present to provide an extra layer of control of gene expression, in addition to Fur. This involves an anti-σ factor and extracytoplasmic function σ-factor, allowing for gene expression in response to the uptake of particular iron chelates. Modified with permission from Annual Review of Microbiology, volume 64 © by Annual Reviews, http://www.annualreviews.org. See Noinaj et al. ( 91 ).

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0010-2015
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Image of FIGURE 4
FIGURE 4

Structure of a representative TBDT. A ribbon diagram of the ferric pyoverdine (FpvA) receptor, bound to pyoverdine. The structure (PDB 2W16) illustrates the 22-stranded β-barrel (green) surrounding the N-terminal “plug” domain (yellow), which is attached to the N-terminal extension signaling domain (red). Pyoverdine bound to the receptor is shown using orange space filling. The side and top views of the structure are illustrated. In the latter view, the pyoverdine has been removed.

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0010-2015
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Image of FIGURE 5
FIGURE 5

Structure of BtuCDF. A ribbon diagram of the BtuCDF complex (PDB 2QI9), representative of the iron-siderophore/cobalamin family of cytoplasmic membrane transporters. The two lobes of the substrate-binding protein BtuF (magenta) are docked on top of the two permease domains (BtuC, monomers colored yellow and green) which are associated with ATP-binding proteins (BtuD, monomers colored red and blue).

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0010-2015
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Image of FIGURE 6
FIGURE 6

Structure of TbpB bound to iron-loaded human transferrin. Depicted is a ribbon diagram of PDB 3VE1 illustrating the binding of human transferrin (also illustrated with transparent surface; N lobe colored blue, C lobe colored yellow, iron depicted with red sphere) by TbpB colored from the N terminus (in blue) to the C terminus (in red). Some relevant domains are indicated. More detail on this structure can be found in Calmettes et al. ( 187 ).

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0010-2015
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Image of FIGURE 7
FIGURE 7

Structures of representative catechol-containing stealth and nonstealth siderophores. Stealth siderophores are not bound by mammalian siderocalin.

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0010-2015
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Tables

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TABLE 1

Examples of heme acquisition systems essential for virulence

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0010-2015
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TABLE 2

Examples of siderophore and transferrin-binding protein-dependent iron acquisition systems essential for virulence

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0010-2015
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TABLE 3

Examples of inorganic iron uptake systems essential for virulence

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0010-2015

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