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(Journal of Leukocyte Biology. 2007;81:393-400.)
© 2007 by Society for Leukocyte Biology

The struggle for iron: gastrointestinal microbes modulate the host immune response during infection

Troy A. Markel*, Paul R. Crisostomo*, Meijing Wang*, Christine M. Herring*, Kirstan K. Meldrum*, Keith D. Lillemoe* and Daniel R. Meldrum*,{dagger},{ddagger},1

* Departments of Surgery and
{dagger} Cellular and Integrative Physiology, and
{ddagger} Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana, USA

1 Correspondence: Departments of Surgery and Cellular and Integrative Physiology and Center for Immunobiology, Indiana University School of Medicine, 545 Barnhill Drive, Emerson Hall 215, Indianapolis, IN 46202, USA. E-mail: dmeldrum{at}iupui.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 GASTROINTESTINAL IMMUNE RESPONSE
 THE ROLE OF IRON...
 HOST IRON ABSORPTION
 MICROBIAL IRON SEQUESTRATION AND...
 CONCLUSION
 REFERENCES
 
The gastrointestinal track is one source of potential bacterial entry into the host, and the local immune system at the mucosal border is paramount in establishing host immune tolerance and the immune response to invading organisms. Macrophages use iron for production of hydroxy-radical and superoxide reactions, which are necessary for microbial killing. Presumably, as a survival strategy, bacteria, which also require iron for survival, have adapted the ability to sequester iron from the host, thereby limiting the availability to macrophages. As current modes of antimicrobial therapy are evolving, examination of nontraditional therapies is emerging. One such potential therapy involves altering the bacterial micronutrient iron concentration. Necrotizing enterocolitis is a clinical condition where such a strategy makes intuitive sense. This review will describe the immune response to gastrointestinal infection, the mechanisms that the gastrointestinal system uses to absorb intraluminal iron, and the critical role iron plays in the infectious process.

Key Words: absorption • macrophage • chelation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
GASTROINTESTINAL IMMUNE RESPONSE
 THE ROLE OF IRON...
 HOST IRON ABSORPTION
 MICROBIAL IRON SEQUESTRATION AND...
 CONCLUSION
 REFERENCES
 
The acute inflammatory response is seen as the body’s way of optimizing the immune system to handle stress or infection. During such a response, a variety of cytokines is released into the local tissues and circulation, and immune cells such as lymphocytes, macrophages, and mast cells are activated to combat the offending agent. Furthermore, the host may alter the micronutrient environment to deprive invading organisms of micronutrients that are essential for replication [1 ].

Sepsis, viewed as a more extensive version of the acute inflammatory response, has led to increased rates of acute and chronic morbidity and mortality over recent years, despite advances in clinical and critical care medicine. In the United States, there are over one-half million cases of sepsis annually and a death rate of 35–65% [2 3 4 ]. Polymicrobial sepsis is associated with immunosuppression, associated with a predominance of inflammatory cytokines, and a profound loss of lymphocytes via apoptosis [5 ].

The gastrointestinal track is viewed as a prominent source for bacterial entry into the host in certain patient populations, particularly those suffering from infectious colitis, necrotizing enterocolitis, or intestinal ischemia. Commensal bacteria existing within the intestine provide essential nutrients to the epithelium and promote healthy immune responses in the gut. However, these bacteria can become invasive pathogens when they acquire genetic material encoding virulence factors or during times of host mucosal barrier breakdown. Studies have shown that animals void of intestinal bacteria tolerate intestinal strangulation and survive longer than their bacterial-cultured counterparts [6 ]. Others have noted that gram-negative bacteria translocate at a much higher rate than do gram-positive and anaerobic organisms [7 ] and that certain drugs, including enalapril [8 ] and catecholamines [9 ], can affect bacterial replication and translocation.

As bacteria become resistant to current antibiotics, other modalities of treatment are being explored. Attempts at neutralizing the effects of various proinflammatory mediators such as TNF-{alpha} and IL-1, while encouraging the expression of various anti-inflammatory cytokines such as IL-10, have thus far proven unsuccessful [2 , 3 , 10 11 12 ]. Therefore, other modalities of the immune system and bacterial modulation need to be explored. One potential therapy entails altering the host’s micronutrient iron concentration. As a method of adaptation, bacteria have developed the ability to acquire iron from hosts via chelators and other iron transport systems [13 14 15 16 ]. Competition between hosts and microbes for iron may lead to the development of infection [17 ], and modulation of these microbial iron acquisition pathways may provide beneficial insight for sepsis therapy.

The purpose of this manuscript is to review the existing literature involving the local immune response to gastrointestinal infection. Furthermore, the mechanisms that the gastrointestinal system uses to absorb intraluminal iron and the role iron plays in this infectious process will be reviewed. Finally, the current literature about bacterial iron chelation, the mechanisms in which bacteria process iron, and the potential therapies to inhibit iron sequestration will be explored.


   GASTROINTESTINAL IMMUNE RESPONSE
TOP
 ABSTRACT
 INTRODUCTION
 GASTROINTESTINAL IMMUNE RESPONSE
THE ROLE OF IRON...
 HOST IRON ABSORPTION
 MICROBIAL IRON SEQUESTRATION AND...
 CONCLUSION
 REFERENCES
 
The gastrointestinal system is a unique immunological system in that it is one of a few that is exposed constantly to harmful bacteria and their toxins. These toxins, when released into the circulation, result in an inflammatory response. The colon is heavily colonized with bacteria, but the small bowel contains several magnitudes-less bacteria than that found in the colon [18 ]. Commensal bacteria are usually limited to the intestinal lumen, mainly associating with mucous components, while the crypt containing intestinal stem cells are rather sterile. Direct binding of bacteria to epithelial cells is usually inhibited in normal mucosa [19 , 20 ]. During gastrointestinal immune homeostasis, noninflammatory innate-immune signals provided by innocuous or commensal bacteria seem to play pertinent roles in the induction of regulatory cytokines via regulatory T cell function and other unknown mechanisms that enable the establishment of tolerance [21 , 22 ].

The first line of innate defense at the mucosal surface is the presence of gut-associated lymphoid tissue [23 ]. Specialized epithelial cells aid in the translocation of antigens to the dendritic cell-rich subepithelial areas of Peyer’s patches. The expression of secretory Igs, which are produced by the cooperation of secretory epithelial cells expressing the receptor for polymeric Igs, and local J-chain-expressing plasma cells, which produce polymeric Igs, is then activated as an efferent pathway in response to the antigen presentation. The receptor and Ig bind on the basolateral membrane and are transported to the apical surface. The receptor is then cleaved, and the Ig is secreted [24 ]. The localization of the Ig receptor and IgA would suggest that the absorptive columnar cells, and not the Paneth cells are primarily responsible for IgA secretion into the intestine [25 26 27 28 ]. Some would even argue that these same absorptive cells also secrete the Ig receptor.

Recent work, however, has demonstrated that the Ig receptor is located specifically in the small intestinal Paneth cells of the rat [24 ]. These Paneth cells reside at the base of the crypts and fulfill a crucial role in innate immunity by producing several antimicrobial enzymes in addition to the aforementioned Ig receptors [29 , 30 ]. They are located in the direct vicinity of the multipotent stem cells, which require particular protection to ensure their viability and ability to continue to replace the epithelial cell line. If the Paneth cells come into contact with microbes or their antigens, further antimicrobial factors are produced to ward off the threat [31 ].

Paneth cells also produce inflammatory cytokines, which serve to further activate the immune system [32 ] by attracting macrophages and lymphocytes [33 ]. These cells also express receptors such as TLRs [34 ] and nucleotide-binding oligomerization domain proteins [35 ], which allow them to react appropriately when in contact with invading microbes and toxins. In addition, certain enterocytes have the ability to produce antimicrobial molecules, which are believed to contribute to intestinal innate immunity and to the relative sterility of the mucosal surface [23 , 36 , 37 ].

Most of the host’s antimicrobial molecules are cationic antimicrobial molecules and are designed to assure binding to the anionic bacterial surface. These include defensins, cathelicidins, cryptdin-related sequence peptides, chemokines, lysozymes, bactericidal/permeability-increasing proteins, and phospholipase II [23 , 38 ]. Some of these agents act by forming anion conductive channels in microbial cell membranes that depolarize and kill the cell [39 , 40 ]. Likewise, they can form channels in enterocytes that lead to flushing the intestinal crypt and the clinical symptom of diarrhea [41 ]. Furthermore, paracrine-binding of these molecules to enterocytes can activate the NF-{kappa}B and MAPK cascades, which ultimately lead to the production of various inflammatory cytokines, including IL-8, IL-1, GM-CSF, growth-related oncogene, and MCP-1 [42 , 43 ].

Once activated, the immune system uses T cells and macrophages alike to induce eradication of microbial insults. The macrophage, which ingests offending agents into phagolysosomes, then proceeds to kill the microbes via hydroxy-radical and superoxide formation. This process is dependent on iron for completion. Likewise, cytotoxic T cells provide an additional means of microbial eradication. The innate and acquired portions of the immune system cooperate to keep the intestinal epithelium and underlying crypts relatively sterile, thereby providing an adequate environment for intestinal stem cell differentiation.


   THE ROLE OF IRON IN IMMUNITY
TOP
 ABSTRACT
 INTRODUCTION
 GASTROINTESTINAL IMMUNE RESPONSE
 THE ROLE OF IRON...
HOST IRON ABSORPTION
 MICROBIAL IRON SEQUESTRATION AND...
 CONCLUSION
 REFERENCES
 
Iron is a critical component of cellular activity and is essential for cell growth and differentiation, electron transfer, oxygen transport, activation, and detoxification [44 ]. Cellular iron availability alters the proliferation and activation of lymphocytes and NK cells, modulates proliferation and differentiation of T cells, monocytes, and macrophages, interacts with cell-mediated immune effecter pathways, and modulates cytokine activities [45 46 47 48 49 ].

During an acute inflammatory response, serum iron has been shown to decrease, and transferrin and intracellular ferritin production has increased [50 , 51 ]. Inflammatory hypoferremia is likely mediated in part by initiation of the inflammatory cytokine cascade. This was supported in murine studies demonstrating that TNF-{alpha} injections resulted in significantly lower serum iron levels and higher levels of circulating ferritin [52 ]. In addition, elevated IL-6 has been shown to result in hypoferremia, likely as a mechanism to limit bacterial iron availability. Decreased release of iron from ferritin stores and decreased absorption of iron from the intestine are part of this process. Conversely, iron injections were noted to decrease parasite load, lower levels of IL-4 and IL-10, and elevate levels of IFN-{gamma} and inducible NO in animal studies examining Leishmania infection [53 ]. The final hypoferremic response, viewed clinically as the anemia of inflammation or chronic disease, is a result of elevated inflammatory cytokines and decreased anti-inflammatory cytokines.

Studies have also shown a correlation between iron concentration and immune cell function. Neutrophil and macrophage dysfunction has been noted with low iron levels, as evidenced by deficient nitroblue terazoleum reduction and hydrogen peroxide formation in these respective cell lines [54 ]. In addition, certain DNA machinery components, such as ribonucleotide reductase, are iron-dependent [55 ]. Iron levels have also been shown to alter the proliferation of TH1 and TH2 subsets, likely related to the difference in dependence of cells on transferrin-related iron uptake [56 ]. TH2 clones possess larger pools of iron susceptible to chelation, as compared with TH1 cells, making TH1 immune pathways more susceptible to changes in ambient iron concentrations [51 ].

Lactoferrin is also a prominent iron-binding protein and immune modulator. Lactoferrin is present in multiple body fluids, including milk, saliva, and tears [57 ], and is released from neutrophils upon degranulation [58 ]. In the circulation and on mucosal surfaces, lactoferrin is incompletely saturated with iron and therefore can clear iron from the tissues. As such, it functions as a first-line defense molecule against invading organisms through its ability to sequester iron. This notion was supported by a study demonstrating that feeding mice with lactoferrin decreased the endotoxin burden in the intestine, indicating a lower degree of intestinal settlement [59 ]. Cell culture studies have also shown decreased inflammatory cytokine production from Escherichia coli-infected intestinal cells with the addition of lactoferrin [60 ]. Furthermore, the lactoferrin sequence comprises a defensin-like peptide, lactoferricin, which shows microbicidal activity against Candida albicans, Streptococcus mutans, Vibrio cholerae, and various enterobacteria [57 , 58 , 61 62 63 ].

Unphysiologic levels of iron have been associated with other immunological sequelae. This effect is likely a result of differences in iron concentrations and the effect iron has on the cytokine cascade. For example, a certain population of Peruvian infants was seen to have leukocytosis and elevated acute-phase reactants associated with hypoferremia [26 ]. In contrast, high serum iron levels have been associated with increased morbidity and mortality, as supplemental injections of iron dextran into newborns resulted in an increased rate of gram-negative neonatal sepsis that resolved when the injections were stopped [64 ]. Reports also exist demonstrating that adults given supplemental ferrous sulfate had an increased incidence of infection compared with controls [65 ]. Finally, elevated iron stores were attributed to hemodialysis patients having a higher incidence of infection [66 ] and impaired phagocytic functions, and to thalassemia patients having impaired NK cell function [67 , 68 ]. These patients also had reduced CD8+ T cell counts, which also may have contributed to increased susceptibility to infection [69 ].

Despite that many studies have shown increased mortality and infection with elevated iron levels, several studies have shown contradictory results, stating that iron should be supplemented in those who are deficient. One particular controlled study noted that iron fortification of milk prevented certain infections in infants [51 ]. Furthermore, studies in humans have demonstrated that mucocutaneous candidiasis [70 ] and farunculosis [71 ] could be resolved with iron therapy, indicating that low iron levels may be associated with worse outcome. This likely leads one to believe that a delicate balance exists with the iron micronutrient environment. Elevated iron stores provide more available iron to microbes, thereby increasing virulence and microbial growth. Low iron stores, however, lead to host immune dysfunction, as tissue macrophages cannot form iron-catalyzed, oxygen-free radicals to destroy invading microbes.

As the role of iron in sepsis becomes increasingly more noted, many are beginning to study the molecular mechanisms associated with iron flux in cells. Different genetic polymorphisms have been associated with susceptibility to infection [72 ] and would therefore suggest that genes likely aid in the control of the micronutrient flux. For example, the mechanism that macrophages use to compete with intracellular microbes has been revealed. Genetic polymorphisms in a protein termed natural resistance-associated macrophage protein 1 (NRAMP1) have been shown to determine susceptibility to a number of bacteria through modulation of the macrophage micronutrient milieu [1 , 73 ]. Similar homologues have been found in other species, which are capable of transporting iron and other micronutrients across the macrophage cell membrane at rates of 20-fold normal uptake [74 , 75 ].

A strong example of iron flux comes from Mycobacterium-infected phagolysosomes. Early in the course of infection, the lysosome recruits NRAMP1 to increase iron flux for use in superoxide dismutase and catalase redox reactions. In response to the host cell’s up-regulation of iron transport, the Mycobacterium induces production of its own cation transporter to compete with the phagosome for intracellular iron [1 ]. The cell which most effectively uses iron transport mechanisms to sequester iron stores will ultimately survive.


   HOST IRON ABSORPTION
TOP
 ABSTRACT
 INTRODUCTION
 GASTROINTESTINAL IMMUNE RESPONSE
 THE ROLE OF IRON...
 HOST IRON ABSORPTION
MICROBIAL IRON SEQUESTRATION AND...
 CONCLUSION
 REFERENCES
 
Normal physiologic function is critically dependent on iron. Most omnivores obtain their iron from heme products ingested in their diet, further supported by the observation that vegetarians are more prone to iron deficiency. It is generally accepted that heme is not transported into the bloodstream as an intact metalloporphyrin. Rather, heme is absorbed by the enterocyte and broken down. The pools of intracellular iron are then combined and released by the enterocyte into the bloodstream [76 77 78 79 80 ] (Fig. 1 ). Heme is taken into the enterocyte intact, as evidenced by the recovery of intact 59Fe heme from intestinal mucosa after gavage of radiolabeled heme [77 78 79 80 ]. Furthermore, a heme transporter (HCP1) has been characterized on the intestinal microvillus [81 ], and it appears that this method of heme transport is an energy-requiring, active process [82 ].


Figure 1
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  		Figure 1. Mechanisms of enterocyte iron transport from the intraluminal membrane to the basolateral membrane. Iron is absorbed from the luminal surface via different transport channels and receptors. Once processed intracellularly, it is stored or exported via the basolateral membrane-associated iron-regulated protein 1 (IREG-1)/ferroportin transporter. Invading bacteria sequester iron as a strategy to disrupt the host’s immune response to the invasion. A vicious cycle ensues, which results in enterocyte dysfunction, decreased iron absorption, immune dysfunction, and further invasion. Heme is likely taken into the enterocyte intact. A heme transporter [heme carrier protein 1 (HCP1)] has been characterized on the intestinal microvillus, and it appears that this method of heme transport is an energy-requiring, active process. Free iron absorption involves the luminal enterocyte protein divalent metal transporter-1 (DMT-1) and ferrireductase, which reduces iron from the Fe3, to the Fe2, form. DMT-1 expression appears to be highly dependent on the body’s iron status. Other molecules, including the gene mutated in hereditary haemochromatosis (HFE), haphaestin (Hp), and Ireg-1, are also involved in intestinal absorption of iron. Hepcidin, a peptide hormone made in the liver, has been shown to regulate iron stores. This peptide inhibits the intestinal cellular efflux of iron by inhibiting the basolateral iron transporter Ireg-1. It is well-recognized that certain iron forms (Fe2+) exist free in the plasma. This is usually iron that is released from intestinal epithelial cells and tissue macrophages. It is usually quickly picked up by circulating transferrin. At physiologic pH, plasma iron is bound tightly to transferrin in the ferric form. Uptake and internalization of transferrin are followed by iron dissociation and storage. IRE, Iron responsive element.

 
Other studies have shown a 50% increase in heme binding to microvillus preparations during states of iron deficiency, raising the question of a localized brush border heme receptor [83 84 85 86 ]. Kinetic studies of the heme receptor complex showed that the receptor had a high affinity for heme. Further studies showing internalization of heme-coated latex beads [87 , 88 ] and the elimination of heme binding with trypsin [89 , 90 ] supported an endocytotic pathway for heme absorption, thereby demonstrating a second pathway for heme-iron absorption.

Other mechanisms of iron absorption have also been demonstrated. Free iron absorption involves the luminal enterocyte protein DMT-1 and ferrireductase, which reduces iron from the Fe3+ to the Fe2+ form. DMT-1 expression appears to be highly dependent on the body’s iron status. Furthermore, two alternatively spliced transcripts of DMT-1 exist. One of these, which contains an IRE, has been shown to be expressed at a higher level in the duodenum as compared with the non-IRE sequence, thereby suggesting that iron-regulated expression of DMT-1 may be controlled by iron regulatory proteins [91 92 93 ].

Other molecules, including HFE, Hp, and Ireg-1, are also involved in intestinal absorption of iron. The HFE gene has been shown to be defective in those with hemochromatosis [94 ], suggesting that HFE limits the amount of iron absorption. Another intestinal iron transport gene, Hp, was shown to be defective in sex-linked, anemic mice. This gene encoded a protein similar to the copper-containing serum ferroxidase ceruloplasmin [95 ], which has been shown to aid in the release of iron from various tissues [96 97 98 ]. Although recent evidence demonstrated that vesicular transport is involved in shuttling iron from the apical to the basolateral membrane, the predicted structure of Hp suggested that it is not a basolateral enterocyte iron transporter, but rather, that it is associated with one, namely Ireg-1 [99 ] (also referred to as ferroportin-1 [100 ] or metal transporter protein-1 [101 ]). Hp protein has been found throughout the small intestine [102 ], unlike DMT-1 and Ireg-1, which appear to be restricted to the duodenum [99 , 100 ]. Furthermore, it appears that iron stores negligibly affect the expression of Hp [102 ].

Hepcidin, a peptide hormone made in the liver, has also been shown to regulate iron stores. This peptide inhibits the intestinal cellular efflux of iron by inhibiting the basolateral iron transporter Ireg-1. Its expression is increased in inflammation and sepsis, thereby leading to the down-regulation of iron absorption, likely through IL-6-dependent mechanisms [103 ]. This adaptation limits iron availability to invading organisms and therefore, contributes to host defense [104 ].

Hemoglobin and intracellular hepatic, bone marrow, and splenic ferritin stores account for the majority of total body iron. Most iron is bound to transferrin, lactoferrin, ferritin, or hemoglobin, but some iron may be free in plasma [51 ]. It is well recognized that certain iron forms (Fe2+) exist free in the plasma. This is usually iron that is released from intestinal epithelial cells and tissue macrophages. It is usually quickly picked up by circulating transferrin [105 ] (Fig. 1) . At physiologic pH, plasma iron is bound tightly to transferrin in the ferric form. Uptake and internalization of transferrin are followed by iron dissociation and storage. Free iron catalyzes the production of reactive oxygen species, which damages host and intracellular microbe cell membranes through lipid peroxidation [1 ].


   MICROBIAL IRON SEQUESTRATION AND TRANSPORT
TOP
 ABSTRACT
 INTRODUCTION
 GASTROINTESTINAL IMMUNE RESPONSE
 THE ROLE OF IRON...
 HOST IRON ABSORPTION
 MICROBIAL IRON SEQUESTRATION AND...
CONCLUSION
 REFERENCES
 
Iron’s presence on the earth extends back to days prior to oxygen. Iron (Fe III) was available as one of the most primitive electron acceptors in microbial metabolism [106 ]. Microbes residing on the mucosal surfaces of the intestine require iron for survival and key intracellular reactions, as evidenced by iron transport mutant Campylobacter species exhibiting a reduced ability to persist in cell culture [107 ]. As such, certain microbes have adapted to the changing environment by developing mechanisms to compete with their hosts for the much-needed iron. These mechanisms are capable of extracting iron from high-affinity ligands including transferrin and lactoferrin and can be in the form of iron transport systems or iron scavenging siderophores. Microorganisms with transport systems for transferrin or ferritin can extract iron directly from the plasma. These organisms include Haemophilus influenza, Neisseria meningitides, and Neisseria gonorrhoeae [108 ].

The transferrin receptor and transport system are species-specific. Two different transferrin receptor subunits are involved: Tbp1 and Tbp2. Once bound to the extracellular receptors, iron is released from transferrin to the high-affinity receptors and is gated through the outer cellular membrane by a gated pore. Once in the periplasmic space, an iron-binding protein guides the iron through the inner membrane permease, thereby allowing iron to move into the cytoplasm [51 ]. The lactoferrin transport system works in a similar manner.

Bacterial iron transporters allow microorganisms to survive in a specific environment, as evidenced by outer membrane receptors for human transferrin in N. meningitidis not being able to bind bovine or porcine transferrin [105 ]. Of interest, Trypanosoma brucei has multiple coding sequences for different transferrin receptors, thereby allowing it to switch receptors to accommodate different hosts and species [51 ]. It also appears that the type of iron transporter plays a role in the location of infection. Transferrin using bacteria are found typically in plasma and cerebrospinal fluid, whereas lactoferrin using bacteria, such as Helicobacter pylori, are found on mucosal surfaces, such as the respiratory, gastrointestinal, and urogenital tracks [51 , 109 ].

Heme and hemoglobin are other potential iron sources for microorganisms. Hemoglobin in circulating erythrocytes contains more hemoglobin than any other source. Many bacteria have mechanisms designed specifically to elucidate iron stores from these sources. This may happen during hemolysis, when iron stores are released into the plasma, or during cell death, when heme proteins are released onto cell surfaces, such as in the intestine [51 ]. Bacteria, which are able to take up iron from heme, include Yersinia enterocolitica, Yersinia pestis, E. coli, V. cholerae, and H. influenza [110 111 112 ]. Heme is transported into the bacterial periplasm by a specific heme receptor transporter and is shuttled further into the cytoplasm by a heme-specific protein transport system [113 ].

Heme-binding proteins such as haptoglobin and hemopexin can be bacteriostatic and interfere with microbial acquisition of iron [114 ]. However, some microbes are able to circumvent these host defense mechanisms by using these binding-protein complexes to acquire iron [115 , 116 ]. Other microbes, such as Plasmodium and Bartonnella species, are able to invade erythrocytes to effectively "steal" iron, and Candida species are able to bind and lyse erythrocytes to acquire the intracellular iron stores.

In addition to adaptive transport mechanisms for iron acquisition, bacteria and fungi have developed low molecular weight iron complexing chelation molecules, known as siderophores, which scavenge for host iron, predominantly in the Fe III form, as this type is the most prominent in aerobic environments [51 ]. Commonly siderophores studied include ferrichrome, enterobactin, staphyloferrin A, ferrioxamine, and deferoxamine.

Ferrichrome, for example, binds to the FhuA receptor on gram-negative bacteria. From there, ferrichrome is shuttled across the plasma membrane and into the cell. FhuA protein production is regulated by ambient iron concentrations. Expression is up-regulated in hypoferric conditions and down-regulated in hyperferric conditions, as too much iron can be toxic to DNA [117 ]. The FhuA molecule is composed of multiple ß-pleated sheets, which form a closed barrel. Binding of ferrichrome opens the barrel and allows the intracellular transport of iron [118 ], which is dependent on a proton-motive force from the cytoplasmic membrane. This energy is transported from the cytoplasm via three proteins, namely TonB, ExbB, and ExbD, which are anchored to the microbial cytoplasmic membrane and open channels in the outer membrane [51 ]. FepA, the outer membrane transporter for enterobactin, is quite similar in structure and function [119 ].

Recent studies have begun to look into the molecular pathways that siderophores have on cellular signaling. It is interesting that a common iron chelator, deferoxamine (DFO), has been shown to initiate the inflammatory cascade in the absence of a bacterial source. Studies by Choi et al. [120 ] exposed intestinal epithelial cells to DFO and found that they responded by producing large amounts of IL-8, which has been shown by others to be released from intestinal epithelial cells in response to proinflammatory cytokines [121 ] and cellular stress [122 123 124 ]. They demonstrated that IL-8 production by DFO-stimulated cells is dependent on the MAPK pathway, particularly associated with p38 and ERK1/2 [120 ]. Choi’s group [120 ] also showed that a number of other genes are affected by DFO, including the p450 enzyme family, vascular endothelial growth factor, NK cell transcript 4, guanosine 5'-triphosphate-binding proteins, and various integrins. The intracellular signaling pathway of deferoxamine-induced cytokine expression is not fully elucidated and therefore, needs further study.

Attempts to use iron chelation as therapy for infection have so far had mixed reviews. Messaris et al. [125 ] showed that rats induced with sepsis and subsequently treated with DFO had increased survival and decreased apoptotic cellular signaling pathways. An additional study examining the role of hemoglobin on septic protection found that treatment with deferoxamine and hemoglobin, but not deferoxamine and apoferritin, induced protection in septic animals [126 ]. Conversely, there are reports of increased infection rates with administration of deferoxamine, indicating an unclear role for iron chelation as therapy for sepsis. Further study is needed to explore the signaling mechanisms that DFO uses for chelation and induction of the inflammatory cascade.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 GASTROINTESTINAL IMMUNE RESPONSE
 THE ROLE OF IRON...
 HOST IRON ABSORPTION
 MICROBIAL IRON SEQUESTRATION AND...
 CONCLUSION
REFERENCES
 
Multiple studies have demonstrated that the micronutrient milieu is important to host survival and well-being. Of particular interest, an overabundance of iron has been shown to increase infection rates and is associated with poor outcomes. In addition, low iron concentrations are associated with an impaired immune system, as critical immune cells such as macrophages cannot produce microbial killing enzymes such as hydoxy-radicals.

As gastrointestinal sources of sepsis continue to be problematic, and as enteric microbes continue to adapt to our current modes of treatment, it is obvious that we will need to consider antimicrobial treatment via a different modality. Altering the mucosal micronutrient environment by manipulating host absorption or microbial use provides theoretical modes of future therapy. Further work is needed to determine the appropriate levels of ambient iron needed to keep the host immune system at peak function, while at the same time, preventing microbial proliferation.

Received September 20, 2006; revised October 21, 2006; accepted October 25, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 GASTROINTESTINAL IMMUNE RESPONSE
 THE ROLE OF IRON...
 HOST IRON ABSORPTION
 MICROBIAL IRON SEQUESTRATION AND...
 CONCLUSION
 REFERENCES
 

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