Iron (Fe) is an essential micronutrient for both microbes and their hosts. The biologic importance of Fe derives from its inherent ability to act as a universal redox catalyst, co-opted in a variety of biochemical processes critical to maintain life. Animals evolved several mechanisms to retain and limit Fe availability to pathogenic microbes, a resistance mechanism termed “nutritional immunity.” Likewise, pathogenic microbes coevolved to deploy diverse and efficient mechanisms to acquire Fe from their hosts and in doing so overcome nutritional immunity. In this review, we discuss how the innate immune system regulates Fe metabolism to withhold Fe from pathogenic microbes and how strategies used by pathogens to acquire Fe circumvent these resistance mechanisms.

Iron accounts for an estimated one third of the Earth’s mass, and presumably for this reason it was co-opted early through evolution as the divalent metal of choice for catalysis of a range of redox-based life-supporting reactions. The biologic importance of Fe resides in its intrinsic ability to shift between ferrous (Fe2+) and ferric (Fe3+) states, as well as higher oxidation states, via reversible exchange of electrons with electrophile or nucleophile molecules, respectively (1). Most forms of life evolved strategies to acquire Fe from their immediate environment, a tactic of particular relevance in the context of host–microbial interactions, where competition for limited Fe resources emerged as an evolutionary conserved host defense strategy against infection in plants (2) and animals (35) as well as a microbial virulence factor (6).

In mammals, the large majority of Fe exists in the form of heme, a hydrophobic Fe-based compound in which four methane-bridged pyrroles form a tetrapyrrole ring that binds Fe through nitrogen atoms (7, 8). Heme is used as a prosthetic group of proteins (i.e., hemoproteins) where Fe is deployed to exchange electrons and catalyze essential biochemical processes, such as the transport and storage of gaseous molecules, microbicidal activity, or energy metabolism. The major pool of heme is contained in hemoglobin (Hb) in RBC, a prime target for pathogens in search of this essential resource.

Although essential to support life, Fe can be deleterious when allowed to exchange electrons in an unrestrained manner with hydrogen peroxide (H2O2) (9), leading to the production of hydroxyl radicals and hydroxide ions via Fenton chemistry. This eventually leads to the production of hydroxyl radicals, which oxidize proteins, lipids, and DNA as well as cellular organelles, leading to oxidative stress and cellular damage. This potentially damaging process is controlled via cell-autonomous and systemic mechanisms that regulate the relative rate of cellular Fe import versus export as well as Fe subcellular localization (5). These regulatory mechanisms are critical to decouple Fe withholding from pathogens from Fe toxicity and cellular damage.

Several evolutionarily conserved mechanisms are operational in mammals to withhold Fe from pathogens and confer resistance to infectious diseases, a defense strategy termed “nutritional immunity” (10, 11). Although similar mechanisms exist to limit the availability of other micronutrients to pathogenic microorganisms, this review focuses on how innate immunity restricts Fe supply to pathogens and how pathogens overcome this resistance mechanism.

Infections are initiated in most cases at epithelial barriers, encompassing the physical transition of microbes into the body of their hosts. This is associated with a major constraint, in that Fe is required to support microbial expansion, and, as such, infection relies strictly on the capacity of pathogenic microorganisms to acquire this essential nutrient from their hosts. Presumably, this explains why most pathogens evolved a variety of strategies aimed at diverting Fe from their hosts into their own metabolic pathways, whereas hosts coevolved strategies to restrict pathogens from accessing Fe (36). This fierce competition for scarce Fe availability dictates to some extent the establishment, progression, and outcome of infections.

Mammals acquire Fe2+ from the diet via a mechanism assisted by the divalent metal transporter ion transporter 1 (DMT1) expressed by duodenum enterocytes (12, 13). Although sufficient to compensate for physiologic loss of Fe associated with epithelial shedding or bleeding, dietary Fe fails to match the amounts needed to support heme biosynthesis associated with erythropoiesis as well as other biologic processes sustaining homeostasis (14). This is circumvented by the recycling of the Fe contained in the heme groups of Hb inside RBC (1416), achieved largely via the continuous engulfment and digestion of senescent or damaged RBC by erythrophagocytic macrophages (EM) in the red pulp of the spleen (15) (Fig. 1). This process allows for the Fe contained in the heme groups of Hb to be extracted and directed into the bone marrow to support erythropoiesis, where Fe is inserted in the last step of heme biosynthesis and incorporated into nascent Hb (15) (Fig. 1). With perhaps some exceptions these regulatory mechanisms controlling systemic Fe metabolism are prime targets for Fe hijacking by microbial pathogens in mammals (Fig. 1).

FIGURE 1.

Microbial manipulation of heme-Fe metabolism. EM are generated via a lineage-specific genetic program controlled by the heme-responsive transcription factor SPI-C (100, 101). SPI-C regulates the expression of several effector genes coupling RBC sensing and engulfment with the breakdown of Hb and other RBC components, while sparing heme, which is transported to the cytosol by HRG1 (101, 102). Heme is degraded by heme oxygenase-1 (HMOX1 or HO-1), an inducible heme catabolizing enzyme constitutively expressed by EM (15). This allows for Fe extraction from heme and Fe transport via the cellular Fe exporter solute carrier family 40 member 1 (SLC40A1/ferroportin) (103105). Once secreted, Fe is captured in plasma by transferrin (TF) and delivered via the transferrin receptor-1 (TFR) to erythroblasts in the bone marrow, where Fe is used in the last step of heme biosynthesis and incorporated into nascent Hb (15). Pathogenic microbes evolved several mechanisms that subvert these regulatory mechanisms of Fe metabolism. They can, for example, invade EM to access their heme-Fe content, use siderophores to capture Fe from plasma, acquire Fe bound to TF via microbial transferrin receptors (mTFR), or access heme-Fe by invading RBC. Pathogens can also lyse RBC via hemolysins to access their heme-Fe, or acquire Fe from extracellular Hb or from heme, using microbial Hb and heme receptors, respectively.

FIGURE 1.

Microbial manipulation of heme-Fe metabolism. EM are generated via a lineage-specific genetic program controlled by the heme-responsive transcription factor SPI-C (100, 101). SPI-C regulates the expression of several effector genes coupling RBC sensing and engulfment with the breakdown of Hb and other RBC components, while sparing heme, which is transported to the cytosol by HRG1 (101, 102). Heme is degraded by heme oxygenase-1 (HMOX1 or HO-1), an inducible heme catabolizing enzyme constitutively expressed by EM (15). This allows for Fe extraction from heme and Fe transport via the cellular Fe exporter solute carrier family 40 member 1 (SLC40A1/ferroportin) (103105). Once secreted, Fe is captured in plasma by transferrin (TF) and delivered via the transferrin receptor-1 (TFR) to erythroblasts in the bone marrow, where Fe is used in the last step of heme biosynthesis and incorporated into nascent Hb (15). Pathogenic microbes evolved several mechanisms that subvert these regulatory mechanisms of Fe metabolism. They can, for example, invade EM to access their heme-Fe content, use siderophores to capture Fe from plasma, acquire Fe bound to TF via microbial transferrin receptors (mTFR), or access heme-Fe by invading RBC. Pathogens can also lyse RBC via hemolysins to access their heme-Fe, or acquire Fe from extracellular Hb or from heme, using microbial Hb and heme receptors, respectively.

Close modal

Once confined to the microenvironment of an infected host, pathogenic microorganisms depend critically on their capacity to redirect host Fe into their own metabolic pathways to survive and proliferate. This can be achieved via the expression of a variety of microbially encoded high-affinity Fe-binding molecules known as siderophores (17) (Fig. 1). These are coupled to specific microbial receptors that capture Fe–siderophore complexes and allow for microbial Fe acquisition (6) (Fig. 1). This microbial Fe acquisition strategy is countered by reducing Fe concentration in plasma, a host defense strategy termed hypoferremia (3, 5). Central to this resistance mechanism is the secretion of hepcidin, an acute-phase 25-aa peptide encoded by the HAMP gene (18, 19). Hepcidin binds and triggers ferroportin degradation, inhibiting cellular Fe efflux systemically (18, 20, 21). HAMP transcription is induced in hepatocytes in response to 1) Fe, 2) microbial sensing by pattern recognition receptors (PRRs), or 3) cytokines produced by innate immune cells, including IL-1β, IL-6, or IL-22 (19, 2224). The central contribution of hepcidin for nutritional immunity against extracellular microbes is illustrated by the increased susceptibility of Hamp-deficient (Hamp−/−) mice to infection by extracellular Gram-negative bacteria, such as siderophilic Yersinia enterocolitica, Vibrio vulnificus, or Klebsiella pneumoniae (2527).

Another mechanism by which innate immune responses restrain extracellular pathogens from accessing Fe involves lactoferrin, a member of the transferrin family of Fe-binding proteins that contributes to the antimicrobial activity of breast milk (28, 29). This glycoprotein secreted by macrophages and polymorphonuclear cells at mucosal surfaces binds Fe3+ with high affinity (KD of ∼10−20 M) and in so doing restricts the virulence of a variety of extracellular pathogens (2931). Lactoferrin also modulates the microbicidal activity of innate immune cells against extracellular bacteria, as illustrated for Staphylococcus aureus (32, 33), while reducing mucosal bacterial colonization, as illustrated for Streptococcus mutans in carious lesions (34, 35). Pathogenic bacteria evolved strategies to recapture Fe from lactoferrin (36, 37), for example by importing Fe-loaded lactoferrin via lactoferrin-binding proteins (38, 39).

Although conferring resistance to extracellular pathogens, hypoferremia is associated with a high evolutionary trade-off in that it leads to Fe overload in macrophages and parenchyma cells, interrupting Fe supply to support erythropoiesis, resulting in the development of anemia of inflammation (5). Consistent with this notion, individuals with genetic Fe-overload disorders, such as hemochromatosis, are highly susceptible to infection (4043), and anemia is a clinical hallmark of many types of infection (5). These pathologic trade-offs are countered by tissue damage control mechanisms that limit the deleterious effects of cellular Fe overload (5, 44) via different mechanisms that involve Fe storage and neutralization by ferritin (44, 45).

Ferritins are evolutionary conserved multimeric protein complexes composed of adjustable ratios of heart/H chain (FTH) and liver/L chain (FTL) proteins, encoded by two distinct genes (45, 46). Ferritins acquire and neutralize intracellular Fe2+ from the Fe-chaperone poly(rC)-binding protein 1 (PCBP1) (47). The ferroxidase activity of FTH is critical for the conversion of Fe2+ into Fe3+, allowing the storage of 4500 Fe3+ atoms per ferritin complex (45, 46). Ferritin expression is highly induced, posttranscriptionally, in response to Fe overload (48) as well as transcriptionally through the activation of the NF-κB family of transcription factors downstream of PRRs or cytokine receptors (49, 50). Activation of the transcription factor NF-E2–related factor-2 (Nrf2), in response to oxidative stress, is another important mechanism regulating ferritin expression (51). Induction of ferritin expression is essential to sustain host survival of extracellular bacterial infections (52) as well as Plasmodium infection (53). This protective effect is not associated with modulation of host pathogen load, revealing that ferritin establishes disease tolerance to infection (44, 54, 55).

The general strategy to limit Fe availability to intracellular pathogens consists in reducing intracellular Fe2+ concentration via mechanisms 1) inhibiting extracellular Fe uptake, 2) promoting Fe3+ storage in ferritin, or 3) increasing cellular Fe2+ efflux (5). In macrophages, the main conduit of Fe2+ from endosomes to the cytosol is the divalent metal ion transporter, named originally as natural resistance–associated macrophage protein-1 (Nramp1; also known as Slc11a1) (56, 57). Macrophages lacking Nramp1 activity exhibit higher intracellular Fe content, which is associated with increased pathogen load in endosomes (57, 58). Nramp1 reduces Fe concentration in phagosomes, restricting the vacuolar growth of intracellular pathogens such as Salmonella enterica serovar Typhimurium (Salmonella), Leishmania donovani, and Mycobacteriun bovis, but not Listeria monocytogenes, that exhibit a cytosolic life style (5660). Importantly, C57BL/6 mice carry a loss-of-function mutation in the Nramp1 gene (61), which should be considered when extrapolating from this widely used experimental model system into human disease.

Some well-established strategies used by innate immune cells to confer resistance against intracellular pathogens act indirectly via a reduction of intracellular Fe content and should therefore be included within the conceptual framework of nutritional immunity. For example, generation of (NO•) by inducible NO• synthase (iNOS/NOS2) is a well-established host defense mechanism that confers resistance to Salmonella, Leishmania, or Mycobacteria (62). Briefly, superoxide (•O2) generated by NADPH oxidase (NOX) 2 family member (gp91phox) (63) reacts with NO• and generates peroxinitrate (ONOO), a stable form of reactive nitrogen species (RNS) that is cytotoxic to pathogens and confers resistance to infections. Aside from its intrinsic microbicidal activity, RNS also activate the transcription factor Nrf2, which regulates ferroportin expression, promoting Fe cellular export and reducing intracellular Fe content (64, 65). Importantly, the mechanism by which NO• confers resistance to Salmonella infection in mice (62) relates functionally to the activation of Nrf2 and the induction of ferroportin, withholding Fe from Salmonella (65, 66). To what extent this mechanism contributes to resistance to other intracellular pathogens remains to be established (67).

Although hepcidin-mediated downregulation of ferroportin is probably the major mechanism leading to hypoferremia in response to infection (19), ferroportin expression is inhibited independently of hepcidin in the context of Salmonella infection (68). Whether other intracellular pathogens (67, 69) use similar mechanisms to inhibit ferroportin expression and gain access to Fe remains to be determined.

Other defense strategies reducing intracellular Fe content rely on posttranscriptional regulation of Fe-responsive genes, afforded by the concerted action of Fe regulatory proteins (IRPs) (59). IRPs sense intracellular Fe content and bind cis-regulatory Fe-responsive elements on target mRNAs, including transferrin receptor-1 (TFR1), ferritin, and ferroportin, regulating their stability (59). This regulatory system is important to orchestrate nutritional immunity against intracellular pathogens, as demonstrated by the enhanced virulence of Salmonella infection in mice lacking IRP expression specifically in macrophages (70).

Most of the current knowledge on host defense strategies limiting Fe availability to pathogens relates to mechanisms targeting elemental Fe. However, considering that each RBC contains 1.2 × 109 Fe molecules and that adult healthy humans carry ∼2–3 × 1013 RBC, it is reasonable to envision why pathogens would evolve strategies to tap directly into this almost unlimited Fe resource (6) (Fig. 2). Perhaps the clearest example of such a strategy is the one co-opted by Plasmodium spp., which invade and proliferate inside RBC, accessing their heme-Fe content (71). Whereas Plasmodium spp. can synthetize heme, trypanosomatid protozoan parasites, such as Leishmania spp. and Trypanosoma spp., are natural heme auxotrophs that rely on host heme acquisition and transport for their survival. This occurs via different mechanisms that rely on heme transport by parasite-encoded heme-responsive gene 1 (HRG1/solute carrier family 48 member 1 or SLC48A1) or orthologous genes (72), as demonstrated for Leishmania spp. (73). and for Trypanosoma spp. (74).

FIGURE 2.

Heme-based nutritional immunity. Microbial sensing via PRRs, expressed by innate immune cells, triggers the secretion of cytokines such as IL-6 or IL-22, which induce the expression of HP or HPX in the liver. HP is an acute-phase glycoprotein that displays high affinity for Hb dimers (KD of ≈10−12 M) (106108) and prevents heme release from Hb dimers (109, 110). HPX is also an acute-phase glycoprotein, which displays high affinity for heme (KD of <10−12 M). Albumin, the most abundant heme-binding protein in the plasma, displays affinity toward heme (KD of <10−8 M) (111) and is thought to play a key role in heme scavenging, transferring labile heme in plasma to HPX (112). Although HPX was thought to act essentially to prevent the pathogenic effects of labile heme (79), it also acts as a host defense strategy against invasion by pathogenic and commensal bacteria (81). Hb–HP complexes are recognized by CD163 expressed in macrophages whereas HPX–heme complexes are recognized by the low-density lipoprotein receptor–related protein (LRP)/CD91 expressed in macrophages but also in hepatocytes (113). Upon binding to CD163, Hb–HP complexes undergo endocytosis and are targeted for lysosomal proteolysis, a process coupled to heme transport into the cytosol, and subsequent targeting of heme for catabolism by heme oxygenase-1 (HO-1). Upon recognition by CD91 in hepatocytes, HPX–heme complexes undergo endocytosis (113) and HPX is recycled, whereas heme is catabolized by HO-1 (113). In both cases, the Fe released via heme catabolism by HO-1 is stored by ferritin, away from microbial pathogens. Although RBC lysis by microbial bacteria is thought to act essentially as an Fe acquisition strategy (6), labile heme generated through this process can disrupt the cytoskeleton dynamics of innate immune cells impairing bacterial phagocytosis via a mechanism involving dedicator of cytokinesis 8 (DOCK8) (114). Similar mechanisms are likely to operate in the context of malaria to impair Plasmodium-infected RBC clearance.

FIGURE 2.

Heme-based nutritional immunity. Microbial sensing via PRRs, expressed by innate immune cells, triggers the secretion of cytokines such as IL-6 or IL-22, which induce the expression of HP or HPX in the liver. HP is an acute-phase glycoprotein that displays high affinity for Hb dimers (KD of ≈10−12 M) (106108) and prevents heme release from Hb dimers (109, 110). HPX is also an acute-phase glycoprotein, which displays high affinity for heme (KD of <10−12 M). Albumin, the most abundant heme-binding protein in the plasma, displays affinity toward heme (KD of <10−8 M) (111) and is thought to play a key role in heme scavenging, transferring labile heme in plasma to HPX (112). Although HPX was thought to act essentially to prevent the pathogenic effects of labile heme (79), it also acts as a host defense strategy against invasion by pathogenic and commensal bacteria (81). Hb–HP complexes are recognized by CD163 expressed in macrophages whereas HPX–heme complexes are recognized by the low-density lipoprotein receptor–related protein (LRP)/CD91 expressed in macrophages but also in hepatocytes (113). Upon binding to CD163, Hb–HP complexes undergo endocytosis and are targeted for lysosomal proteolysis, a process coupled to heme transport into the cytosol, and subsequent targeting of heme for catabolism by heme oxygenase-1 (HO-1). Upon recognition by CD91 in hepatocytes, HPX–heme complexes undergo endocytosis (113) and HPX is recycled, whereas heme is catabolized by HO-1 (113). In both cases, the Fe released via heme catabolism by HO-1 is stored by ferritin, away from microbial pathogens. Although RBC lysis by microbial bacteria is thought to act essentially as an Fe acquisition strategy (6), labile heme generated through this process can disrupt the cytoskeleton dynamics of innate immune cells impairing bacterial phagocytosis via a mechanism involving dedicator of cytokinesis 8 (DOCK8) (114). Similar mechanisms are likely to operate in the context of malaria to impair Plasmodium-infected RBC clearance.

Close modal

Bacterial pathogens co-opted alternative strategies, which rely on the expression of hemolysins, damaging RBC and releasing their Hb content (Fig. 2). Extracellular Hb dissociates readily into dimers, which are prone to auto-oxidation, releasing their prosthetic heme groups and generating labile heme (75, 76) (Fig. 2). Gram-negative pathogenic bacteria, such as Y. enterocolitica, Shigella, Escherichia coli O157:H7, Yersinia pestis, or Haemophilus influenzae, express outer membrane Hb and/or heme receptors, whereas Y. pestis, Pseudomonas aeruginosa, and Serratia marcescens secrete hemophores that bind extracellular heme (3, 77). These are recognized by outer membrane TonB-dependent heme, hemoprotein, and hemophore receptors, respectively, which shuttle heme to the bacterial periplasm to be transported into the cytosol by specific ABC protein–dependent periplasmic permeases (3, 77). The cytosolic heme is used to extract Fe by heme oxygenases (3, 77). Gram-positive pathogenic bacteria, such as S. aureus, Bacillus anthracis, and Corynebacterium diphtheriae, also rely on heme acquisition systems to establish infection (78).

Acquisition of labile heme from plasma is countered by the acute-phase heme scavenger hemopexin (HPX) (Fig. 2). Although thought to act exclusively as part of a protective response limiting the pathogenic effects of labile heme (79, 80), HPX also acts as a component of nutritional immunity, limiting heme availability to extracellular bacteria, as demonstrated for Citrobacter rodentium and commensal E. coli (81). This defense strategy is orchestrated by IL-22, a cytokine produced by innate immune cells, that acts on hepatocytes, where it induces the expression of HPX (81) (Fig. 2). Whether Hb scavenging by haptoglobin (HP) also acts as a component of nutritional immunity is likely, but this remains to be established.

Some highly virulent bacterial pathogens deploy “Fe piracy” strategies, hijacking Fe or heme from host Fe- or heme-binding molecules and in so doing subvert nutritional immunity (8284). For example, Neisseria spp., H. influenzae, and Moraxella catarrhalis deploy transferrin-binding proteins (TbpA/TbpB) that capture host Fe-bound transferrin (6). Other bacteria express lactoferrin receptors to capture Fe3+-bound lactoferrin (6). Most bacterial pathogens secrete siderophores that bind Fe3+ at extremely high affinity and can (re)capture Fe from host Fe-binding proteins such as transferrin or lactoferrin (85). This strategy is perhaps best illustrated for enterobactin, a prototypical siderophore produced by Enterobacteriaceae (85). Siderophores such as enterobactin are essential for Fe acquisition by many bacterial pathogens such as E. coli or Salmonella, a strategy coupled to the expression of siderophore receptors by these pathogens (85, 86).

Innate immune cells secrete molecules that impair the action of microbial siderophores, such as lipocalin 2 (Lcn2/neutrophil gelatinase-associated lipocalin; NGAL, siderocalin) (87). Lcn2 is a soluble peptide secreted by activated polymorphonuclear cells, monocytes/macrophages, and epithelial cells in response to the engagement of PRRs. Lcn2 binds siderophores such as enterobactin and delivers Lcn2–Fe–siderophore complexes to host cells via the Lcn2 receptor (88, 89), inhibiting bacterial uptake of Fe-laden siderophores (87, 90). This defense strategy is not specific to bacteria in that it also acts against protozoan parasites, as illustrated for example for Plasmodium infection (91). This defense strategy is countered by some pathogens via a mechanism that relies on the production of modified siderophores, such as, for example, the glycosylated enterobactin salmochelin or the production of structurally unrelated siderophores not bound by Lnc2 (9294). The variety of siderophores produced by any given bacterial strain provides a high level of functional redundancy reflecting the enormous selective pressure imposed on pathogens to acquire Fe under the Fe-withholding conditions of the host (9597).

Pathogen sensing via PRRs activates resistance mechanisms in innate immune cells, which rely on the microbicidal activity of reactive oxygen species (ROS) and RNS (Fig. 3). Additionally, pathogen sensing via PRRs promotes resistance mechanisms in innate immune cells, which withhold heme-Fe from pathogens (15) (Fig. 3). Importantly, this defense strategy modulates cellular Fe content, which impacts the microbicidal activity of innate immune cells such as macrophages (30, 98, 99). This argues for a tight integration between these two resistance responses, as suggested further by the observation that in some instances the microbicidal activity of ROS and RNS relies on the induction of effector mechanisms preventing pathogens from accessing Fe and possibly heme (65) (Fig. 3). This suggests that the microbicidal activity of innate immune cells involves a functional interplay between cytotoxic and Fe-depriving mechanisms.

FIGURE 3.

Integration of nutritional immunity as an innate resistance mechanism. Pathogen sensing via PRR signaling (S1) activates the expression of effector genes conferring resistance to pathogens. These encode molecules (E1) such as NOX2 and NOS2 that induce intrinsic microbicidal activity via ROS and RNS (A), as well as molecules (E2) withholding heme-Fe from pathogens, such as ferroportin (15) (B). ROS and RNS can regulate ferroportin and nutritional immunity via activation of the transcription factor Nrf2 (E3) to optimize resistance to infections (C).

FIGURE 3.

Integration of nutritional immunity as an innate resistance mechanism. Pathogen sensing via PRR signaling (S1) activates the expression of effector genes conferring resistance to pathogens. These encode molecules (E1) such as NOX2 and NOS2 that induce intrinsic microbicidal activity via ROS and RNS (A), as well as molecules (E2) withholding heme-Fe from pathogens, such as ferroportin (15) (B). ROS and RNS can regulate ferroportin and nutritional immunity via activation of the transcription factor Nrf2 (E3) to optimize resistance to infections (C).

Close modal

Although the concept of nutritional immunity was proposed over 40 years ago (10), this defense strategy has not gained much attention among immunologists. This is paradoxical because one of the central resistance mechanisms deployed by innate immunity relies on starving pathogens from essential micronutrients required for their proliferation. This defense strategy is particularly relevant for Fe, a micronutrient essential for virtually all microbial pathogens. Given that the large majority of Fe in mammals is contained inside heme, microbial pathogens evolved to capture heme as the means to access Fe whereas hosts coevolved to withhold heme from microbial pathogens. This strategy is illustrated by the finding that some acute-phase proteins such as the heme scavenger HPX are a central component of nutritional immunity that confers resistance to bacterial infections. This defense strategy must be coupled to tissue damage control mechanisms that detoxify heme-Fe and contribute to establishing disease tolerance to infections. To what extent this coupling of nutritional immunity and disease tolerance acts as a universal host defense strategy against infections remains to be established.

We thank Joseph Pickard for critical review of the manuscript.

This work was supported by National Institutes of Health Grants DK61707 and DK091191 (to G.N.). M.P.S. is supported by Fundação Calouste Gulbenkian, Fundação para a Ciência e Tecnologia Grant PTDC/IMI-IMU/5723/2014.

Abbreviations used in this article:

EM

erythrophagocytic macrophage

Fe

iron

Fe2+

ferrous

Fe3+

ferric

Hb

hemoglobin

HMOX1

HO-1, heme oxygenase-1

HP

haptoglobin

HPX

hemopexin

IRP

Fe regulatory protein

Lcn2

lipocalin 2

Nramp1

natural resistance–associated macrophage protein-1

Nrf2

NF-E2–related factor-2

PRR

pattern recognition receptor

RNS

reactive nitrogen species

ROS

reactive oxygen species.

1
Chapman
,
S. K.
,
S.
Daff
,
A. W.
Munro
.
1997
.
Heme: the most versatile redox centre in biology?
Metal Sites in Proteins and Models
88
:
39
70
.
2
Verbon
,
E. H.
,
P. L.
Trapet
,
I. A.
Stringlis
,
S.
Kruijs
,
P. A. H. M.
Bakker
,
C. M. J.
Pieterse
.
2017
.
Iron and immunity.
Annu. Rev. Phytopathol.
55
:
355
375
.
3
Cassat
,
J. E.
,
E. P.
Skaar
.
2013
.
Iron in infection and immunity.
Cell Host Microbe
13
:
509
519
.
4
Hood
,
M. I.
,
E. P.
Skaar
.
2012
.
Nutritional immunity: transition metals at the pathogen–host interface.
Nat. Rev. Microbiol.
10
:
525
537
.
5
Soares
,
M. P.
,
G.
Weiss
.
2015
.
The iron age of host–microbe interactions.
EMBO Rep.
16
:
1482
1500
.
6
Palmer
,
L. D.
,
E. P.
Skaar
.
2016
.
Transition metals and virulence in bacteria.
Annu. Rev. Genet.
50
:
67
91
.
7
Tsiftsoglou
,
A. S.
,
A. I.
Tsamadou
,
L. C.
Papadopoulou
.
2006
.
Heme as key regulator of major mammalian cellular functions: molecular, cellular, and pharmacological aspects.
Pharmacol. Ther.
111
:
327
345
.
8
Poulos
,
T. L.
2007
.
The Janus nature of heme.
Nat. Prod. Rep.
24
:
504
510
.
9
Kumar
,
S.
,
U.
Bandyopadhyay
.
2005
.
Free heme toxicity and its detoxification systems in human.
Toxicol. Lett.
157
:
175
188
.
10
Weinberg
,
E. D.
1975
.
Nutritional immunity. Host’s attempt to withhold iron from microbial invaders.
JAMA
231
:
39
41
.
11
Oppenheimer
,
S. J.
2001
.
Iron and its relation to immunity and infectious disease.
J. Nutr.
131
(
2S-2
):
616S
633S
.
12
Gunshin
,
H.
,
Y.
Fujiwara
,
A. O.
Custodio
,
C.
Direnzo
,
S.
Robine
,
N. C.
Andrews
.
2005
.
Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver.
J. Clin. Invest.
115
:
1258
1266
.
13
McKie
,
A. T.
,
D.
Barrow
,
G. O.
Latunde-Dada
,
A.
Rolfs
,
G.
Sager
,
E.
Mudaly
,
M.
Mudaly
,
C.
Richardson
,
D.
Barlow
,
A.
Bomford
, et al
.
2001
.
An iron-regulated ferric reductase associated with the absorption of dietary iron.
Science
291
:
1755
1759
.
14
Muckenthaler
,
M. U.
,
S.
Rivella
,
M. W.
Hentze
,
B.
Galy
.
2017
.
A red carpet for iron metabolism.
Cell
168
:
344
361
.
15
Soares
,
M. P.
,
I.
Hamza
.
2016
.
Macrophages and iron metabolism.
Immunity
44
:
492
504
.
16
Ganz
,
T.
,
E.
Nemeth
.
2015
.
Iron homeostasis in host defence and inflammation.
Nat. Rev. Immunol.
15
:
500
510
.
17
Crosa
,
J. H.
,
C. T.
Walsh
.
2002
.
Genetics and assembly line enzymology of siderophore biosynthesis in bacteria.
Microbiol. Mol. Biol. Rev.
66
:
223
249
.
18
Nemeth
,
E.
,
M. S.
Tuttle
,
J.
Powelson
,
M. B.
Vaughn
,
A.
Donovan
,
D. M.
Ward
,
T.
Ganz
,
J.
Kaplan
.
2004
.
Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.
Science
306
:
2090
2093
.
19
Drakesmith
,
H.
,
A. M.
Prentice
.
2012
.
Hepcidin and the iron-infection axis.
Science
338
:
768
772
.
20
Ganz
,
T.
,
E.
Nemeth
.
2011
.
Hepcidin and disorders of iron metabolism.
Annu. Rev. Med.
62
:
347
360
.
21
Rodriguez
,
R.
,
C. L.
Jung
,
V.
Gabayan
,
J. C.
Deng
,
T.
Ganz
,
E.
Nemeth
,
Y.
Bulut
.
2014
.
Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6.
Infect. Immun.
82
:
745
752
.
22
Loréal
,
O.
,
T.
Cavey
,
E.
Bardou-Jacquet
,
P.
Guggenbuhl
,
M.
Ropert
,
P.
Brissot
.
2014
.
Iron, hepcidin, and the metal connection.
Front. Pharmacol.
5
:
128
.
23
Armitage
,
A. E.
,
L. A.
Eddowes
,
U.
Gileadi
,
S.
Cole
,
N.
Spottiswoode
,
T. A.
Selvakumar
,
L. P.
Ho
,
A. R.
Townsend
,
H.
Drakesmith
.
2011
.
Hepcidin regulation by innate immune and infectious stimuli.
Blood
118
:
4129
4139
.
24
Nemeth
,
E.
,
E. V.
Valore
,
M.
Territo
,
G.
Schiller
,
A.
Lichtenstein
,
T.
Ganz
.
2003
.
Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein.
Blood
101
:
2461
2463
.
25
Arezes
,
J.
,
G.
Jung
,
V.
Gabayan
,
E.
Valore
,
P.
Ruchala
,
P. A.
Gulig
,
T.
Ganz
,
E.
Nemeth
,
Y.
Bulut
.
2015
.
Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus.
Cell Host Microbe
17
:
47
57
.
26
Stefanova
,
D.
,
A.
Raychev
,
J.
Arezes
,
P.
Ruchala
,
V.
Gabayan
,
M.
Skurnik
,
B. J.
Dillon
,
M. A.
Horwitz
,
T.
Ganz
,
Y.
Bulut
,
E.
Nemeth
.
2017
.
Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron.
Blood
130
:
245
257
.
27
Michels
,
K. R.
,
Z.
Zhang
,
A. M.
Bettina
,
R. E.
Cagnina
,
D.
Stefanova
,
M. D.
Burdick
,
S.
Vaulont
,
E.
Nemeth
,
T.
Ganz
,
B.
Mehrad
.
2017
.
Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia.
JCI Insight
2
:
e92002
.
28
Brocke
,
K. S.
,
G.
Neu-Yilik
,
N. H.
Gehring
,
M. W.
Hentze
,
A. E.
Kulozik
.
2002
.
The human intronless melanocortin 4-receptor gene is NMD insensitive.
Hum. Mol. Genet.
11
:
331
335
.
29
Brock
,
J. H.
2002
.
The physiology of lactoferrin.
Biochem. Cell Biol.
80
:
1
6
.
30
Nairz
,
M.
,
D.
Haschka
,
E.
Demetz
,
G.
Weiss
.
2014
.
Iron at the interface of immunity and infection.
Front. Pharmacol.
5
:
152
.
31
Kontoghiorghes
,
G. J.
,
E. D.
Weinberg
.
1995
.
Iron: mammalian defense systems, mechanisms of disease, and chelation therapy approaches.
Blood Rev.
9
:
33
45
.
32
Hwang
,
S. A.
,
M. L.
Kruzel
,
J. K.
Actor
.
2014
.
Immunomodulatory effects of recombinant lactoferrin during MRSA infection.
Int. Immunopharmacol.
20
:
157
163
.
33
Guillén
,
C.
,
I. B.
McInnes
,
D. M.
Vaughan
,
S.
Kommajosyula
,
P. H.
Van Berkel
,
B. P.
Leung
,
A.
Aguila
,
J. H.
Brock
.
2002
.
Enhanced Th1 response to Staphylococcus aureus infection in human lactoferrin-transgenic mice.
J. Immunol.
168
:
3950
3957
.
34
Velusamy
,
S. K.
,
K.
Markowitz
,
D. H.
Fine
,
K.
Velliyagounder
.
2016
.
Human lactoferrin protects against Streptococcus mutans-induced caries in mice.
Oral Dis.
22
:
148
154
.
35
Ward
,
P. P.
,
M.
Mendoza-Meneses
,
P. W.
Park
,
O. M.
Conneely
.
2008
.
Stimulus-dependent impairment of the neutrophil oxidative burst response in lactoferrin-deficient mice.
Am. J. Pathol.
172
:
1019
1029
.
36
Olakanmi
,
O.
,
B.
Kesavalu
,
M. Y.
Abdalla
,
B. E.
Britigan
.
2013
.
Iron acquisition by Mycobacterium tuberculosis residing within myeloid dendritic cells.
Microb. Pathog.
65
:
21
28
.
37
Ge
,
R.
,
X.
Sun
.
2014
.
Iron acquisition and regulation systems in Streptococcus species.
Metallomics
6
:
996
1003
.
38
Morgenthau
,
A.
,
A.
Beddek
,
A. B.
Schryvers
.
2014
.
The negatively charged regions of lactoferrin binding protein B, an adaptation against anti-microbial peptides.
PLoS One
9
:
e86243
.
39
Noinaj
,
N.
,
C. N.
Cornelissen
,
S. K.
Buchanan
.
2013
.
Structural insight into the lactoferrin receptors from pathogenic Neisseria.
J. Struct. Biol.
184
:
83
92
.
40
Barton
,
J. C.
,
R. T.
Acton
.
2009
.
Hemochromatosis and Vibrio vulnificus wound infections.
J. Clin. Gastroenterol.
43
:
890
893
.
41
Bergmann
,
T. K.
,
K.
Vinding
,
H.
Hey
.
2001
.
Multiple hepatic abscesses due to Yersinia enterocolitica infection secondary to primary haemochromatosis.
Scand. J. Gastroenterol.
36
:
891
895
.
42
Höpfner
,
M.
,
R.
Nitsche
,
A.
Rohr
,
D.
Harms
,
S.
Schubert
,
U. R.
Fölsch
.
2001
.
Yersinia enterocolitica infection with multiple liver abscesses uncovering a primary hemochromatosis.
Scand. J. Gastroenterol.
36
:
220
224
.
43
Wang
,
S. C.
,
K. H.
Lin
,
J. P.
Chern
,
M. Y.
Lu
,
S. T.
Jou
,
D. T.
Lin
,
K. S.
Lin
.
2003
.
Severe bacterial infection in transfusion-dependent patients with thalassemia major.
Clin. Infect. Dis.
37
:
984
988
.
44
Soares
,
M. P.
,
R.
Gozzelino
,
S.
Weis
.
2014
.
Tissue damage control in disease tolerance.
Trends Immunol.
35
:
483
494
.
45
Gozzelino
,
R.
,
M. P.
Soares
.
2014
.
Coupling heme and iron metabolism via ferritin H chain.
Antioxid. Redox Signal.
20
:
1754
1769
.
46
Harrison
,
P. M.
,
P.
Arosio
.
1996
.
The ferritins - molecular properties, iron storage function and cellular regulation.
Biochim. Biophys. Acta
1275
:
161
203
.
47
Shi
,
H.
,
K. Z.
Bencze
,
T. L.
Stemmler
,
C. C.
Philpott
.
2008
.
A cytosolic iron chaperone that delivers iron to ferritin.
Science
320
:
1207
1210
.
48
Hentze
,
M. W.
,
S. W.
Caughman
,
T. A.
Rouault
,
J. G.
Barriocanal
,
A.
Dancis
,
J. B.
Harford
,
R. D.
Klausner
.
1987
.
Identification of the iron-responsive element for the translational regulation of human ferritin mRNA.
Science
238
:
1570
1573
.
49
Kwak
,
E. L.
,
D. A.
Larochelle
,
C.
Beaumont
,
S. V.
Torti
,
F. M.
Torti
.
1995
.
Role for NF-κB in the regulation of ferritin H by tumor necrosis factor-α.
J. Biol. Chem.
270
:
15285
15293
.
50
Miller
,
L. L.
,
S. C.
Miller
,
S. V.
Torti
,
Y.
Tsuji
,
F. M.
Torti
.
1991
.
Iron-independent induction of ferritin H chain by tumor necrosis factor.
Proc. Natl. Acad. Sci. USA
88
:
4946
4950
.
51
Pietsch
,
E. C.
,
J. Y.
Chan
,
F. M.
Torti
,
S. V.
Torti
.
2003
.
Nrf2 mediates the induction of ferritin H in response to xenobiotics and cancer chemopreventive dithiolethiones.
J. Biol. Chem.
278
:
2361
2369
.
52
Weis
,
S.
,
A. R.
Carlos
,
M. R.
Moita
,
S.
Singh
,
B.
Blankenhaus
,
S.
Cardoso
,
R.
Larsen
,
S.
Rebelo
,
S.
Schäuble
,
L.
Del Barrio
, et al
.
2017
.
Metabolic adaptation establishes disease tolerance to sepsis.
Cell
169
:
1263
1275.e14
.
53
Gozzelino
,
R.
,
B. B.
Andrade
,
R.
Larsen
,
N. F.
Luz
,
L.
Vanoaica
,
E.
Seixas
,
A.
Coutinho
,
S.
Cardoso
,
S.
Rebelo
,
M.
Poli
, et al
.
2012
.
Metabolic adaptation to tissue iron overload confers tolerance to malaria.
Cell Host Microbe
12
:
693
704
.
54
Soares
,
M. P.
,
L.
Teixeira
,
L. F.
Moita
.
2017
.
Disease tolerance and immunity in host protection against infection.
Nat. Rev. Immunol.
17
:
83
96
.
55
Medzhitov
,
R.
,
D. S.
Schneider
,
M. P.
Soares
.
2012
.
Disease tolerance as a defense strategy.
Science
335
:
936
941
.
56
Vidal
,
S.
,
M. L.
Tremblay
,
G.
Govoni
,
S.
Gauthier
,
G.
Sebastiani
,
D.
Malo
,
E.
Skamene
,
M.
Olivier
,
S.
Jothy
,
P.
Gros
.
1995
.
The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene.
J. Exp. Med.
182
:
655
666
.
57
Jabado
,
N.
,
A.
Jankowski
,
S.
Dougaparsad
,
V.
Picard
,
S.
Grinstein
,
P.
Gros
.
2000
.
Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane.
J. Exp. Med.
192
:
1237
1248
.
58
Soe-Lin
,
S.
,
S. S.
Apte
,
B.
Andriopoulos
Jr.
,
M. C.
Andrews
,
M.
Schranzhofer
,
T.
Kahawita
,
D.
Garcia-Santos
,
P.
Ponka
.
2009
.
Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo.
Proc. Natl. Acad. Sci. USA
106
:
5960
5965
.
59
Forbes
,
J. R.
,
P.
Gros
.
2001
.
Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions.
Trends Microbiol.
9
:
397
403
.
60
Haschka
,
D.
,
M.
Nairz
,
E.
Demetz
,
S.
Wienerroither
,
T.
Decker
,
G.
Weiss
.
2015
.
Contrasting regulation of macrophage iron homeostasis in response to infection with Listeria monocytogenes depending on localization of bacteria.
Metallomics
7
:
1036
1045
.
61
Vidal
,
S. M.
,
E.
Pinner
,
P.
Lepage
,
S.
Gauthier
,
P.
Gros
.
1996
.
Natural resistance to intracellular infections: Nramp1 encodes a membrane phosphoglycoprotein absent in macrophages from susceptible (Nramp1 D169) mouse strains.
J. Immunol.
157
:
3559
3568
.
62
Nathan
,
C.
,
M. U.
Shiloh
.
2000
.
Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens.
Proc. Natl. Acad. Sci. USA
97
:
8841
8848
.
63
Yu
,
L.
,
M. T.
Quinn
,
A. R.
Cross
,
M. C.
Dinauer
.
1998
.
Gp91phox is the heme binding subunit of the superoxide-generating NADPH oxidase.
Proc. Natl. Acad. Sci. USA
95
:
7993
7998
.
64
Nairz
,
M.
,
G.
Fritsche
,
P.
Brunner
,
H.
Talasz
,
K.
Hantke
,
G.
Weiss
.
2008
.
Interferon-γ limits the availability of iron for intramacrophage Salmonella typhimurium.
Eur. J. Immunol.
38
:
1923
1936
.
65
Nairz
,
M.
,
U.
Schleicher
,
A.
Schroll
,
T.
Sonnweber
,
I.
Theurl
,
S.
Ludwiczek
,
H.
Talasz
,
G.
Brandacher
,
P. L.
Moser
,
M. U.
Muckenthaler
, et al
.
2013
.
Nitric oxide–mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection.
J. Exp. Med.
210
:
855
873
.
66
Chlosta
,
S.
,
D. S.
Fishman
,
L.
Harrington
,
E. E.
Johnson
,
M. D.
Knutson
,
M.
Wessling-Resnick
,
B. J.
Cherayil
.
2006
.
The iron efflux protein ferroportin regulates the intracellular growth of Salmonella enterica.
Infect. Immun.
74
:
3065
3067
.
67
Paradkar
,
P. N.
,
I.
De Domenico
,
N.
Durchfort
,
I.
Zohn
,
J.
Kaplan
,
D. M.
Ward
.
2008
.
Iron depletion limits intracellular bacterial growth in macrophages.
Blood
112
:
866
874
.
68
Willemetz
,
A.
,
S.
Beatty
,
E.
Richer
,
A.
Rubio
,
A.
Auriac
,
R. J.
Milkereit
,
O.
Thibaudeau
,
S.
Vaulont
,
D.
Malo
,
F.
Canonne-Hergaux
.
2017
.
Iron- and hepcidin-independent downregulation of the iron exporter ferroportin in macrophages during Salmonella infection.
Front. Immunol.
8
:
498
.
69
Moreira
,
A. C.
,
J. V.
Neves
,
T.
Silva
,
P.
Oliveira
,
M. S.
Gomes
,
P. N.
Rodrigues
.
2017
.
Hepcidin-(in)dependent mechanisms of iron metabolism regulation during infection by Listeria and Salmonella.
Infect. Immun.
85
:
e00353-17
.
70
Nairz
,
M.
,
D.
Ferring-Appel
,
D.
Casarrubea
,
T.
Sonnweber
,
L.
Viatte
,
A.
Schroll
,
D.
Haschka
,
F. C.
Fang
,
M. W.
Hentze
,
G.
Weiss
,
B.
Galy
.
2015
.
Iron regulatory proteins mediate host resistance to Salmonella infection.
Cell Host Microbe
18
:
254
261
.
71
Sigala
,
P. A.
,
D. E.
Goldberg
.
2014
.
The peculiarities and paradoxes of Plasmodium heme metabolism.
Annu. Rev. Microbiol.
68
:
259
278
.
72
Rajagopal
,
A.
,
A. U.
Rao
,
J.
Amigo
,
M.
Tian
,
S. K.
Upadhyay
,
C.
Hall
,
S.
Uhm
,
M. K.
Mathew
,
M. D.
Fleming
,
B. H.
Paw
, et al
.
2008
.
Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins.
Nature
453
:
1127
1131
.
73
Huynh
,
C.
,
X.
Yuan
,
D. C.
Miguel
,
R. L.
Renberg
,
O.
Protchenko
,
C. C.
Philpott
,
I.
Hamza
,
N. W.
Andrews
.
2012
.
Heme uptake by Leishmania amazonensis is mediated by the transmembrane protein LHR1.
PLoS Pathog.
8
:
e1002795
.
74
Cabello-Donayre
,
M.
,
S.
Malagarie-Cazenave
,
J.
Campos-Salinas
,
F. J.
Gálvez
,
A.
Rodríguez-Martínez
,
E.
Pineda-Molina
,
L. M.
Orrego
,
M.
Martínez-García
,
M. P.
Sánchez-Cañete
,
A. M.
Estévez
,
J. M.
Pérez-Victoria
.
2016
.
Trypanosomatid parasites rescue heme from endocytosed hemoglobin through lysosomal HRG transporters.
Mol. Microbiol.
101
:
895
908
.
75
Gouveia
,
Z.
,
A. R.
Carlos
,
X.
Yuan
,
F.
Aires-da-Silva
,
R.
Stocker
,
G. J.
Maghzal
,
S. S.
Leal
,
C. M.
Gomes
,
S.
Todorovic
,
O.
Iranzo
, et al
.
2017
.
Characterization of plasma labile heme in hemolytic conditions.
FEBS J.
284
:
3278
3301
.
76
Ferreira
,
A.
,
J.
Balla
,
V.
Jeney
,
G.
Balla
,
M. P.
Soares
.
2008
.
A central role for free heme in the pathogenesis of severe malaria: the missing link?
J. Mol. Med. (Berl.)
86
:
1097
1111
.
77
Wandersman
,
C.
,
I.
Stojiljkovic
.
2000
.
Bacterial heme sources: the role of heme, hemoprotein receptors and hemophores.
Curr. Opin. Microbiol.
3
:
215
220
.
78
Choby
,
J. E.
,
E. P.
Skaar
.
2016
.
Heme synthesis and acquisition in bacterial pathogens.
J. Mol. Biol.
428
:
3408
3428
.
79
Soares
,
M. P.
,
M. T.
Bozza
.
2016
.
Red alert: labile heme is an alarmin.
Curr. Opin. Immunol.
38
:
94
100
.
80
Tolosano
,
E.
,
S.
Fagoonee
,
N.
Morello
,
F.
Vinchi
,
V.
Fiorito
.
2010
.
Heme scavenging and the other facets of hemopexin.
Antioxid. Redox Signal.
12
:
305
320
.
81
Sakamoto
,
K.
,
Y. G.
Kim
,
H.
Hara
,
N.
Kamada
,
G.
Caballero-Flores
,
E.
Tolosano
,
M. P.
Soares
,
J. L.
Puente
,
N.
Inohara
,
G.
Núñez
.
2017
.
IL-22 controls iron-dependent nutritional immunity against systemic bacterial infections.
Sci. Immunol.
2
:
eaai8371
.
82
Dhaenens
,
L.
,
F.
Szczebara
,
M. O.
Husson
.
1997
.
Identification, characterization, and immunogenicity of the lactoferrin-binding protein from Helicobacter pylori.
Infect. Immun.
65
:
514
518
.
83
Moraes
,
T. F.
,
R. H.
Yu
,
N. C.
Strynadka
,
A. B.
Schryvers
.
2009
.
Insights into the bacterial transferrin receptor: the structure of transferrin-binding protein B from Actinobacillus pleuropneumoniae.
Mol. Cell
35
:
523
533
.
84
Morgenthau
,
A.
,
A.
Pogoutse
,
P.
Adamiak
,
T. F.
Moraes
,
A. B.
Schryvers
.
2013
.
Bacterial receptors for host transferrin and lactoferrin: molecular mechanisms and role in host–microbe interactions.
Future Microbiol.
8
:
1575
1585
.
85
Miethke
,
M.
,
M. A.
Marahiel
.
2007
.
Siderophore-based iron acquisition and pathogen control.
Microbiol. Mol. Biol. Rev.
71
:
413
451
.
86
Hantke
,
K.
,
G.
Nicholson
,
W.
Rabsch
,
G.
Winkelmann
.
2003
.
Salmochelins, siderophores of Salmonella enterica and uropathogenic Escherichia coli strains, are recognized by the outer membrane receptor IroN.
Proc. Natl. Acad. Sci. USA
100
:
3677
3682
.
87
Flo
,
T. H.
,
K. D.
Smith
,
S.
Sato
,
D. J.
Rodriguez
,
M. A.
Holmes
,
R. K.
Strong
,
S.
Akira
,
A.
Aderem
.
2004
.
Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron.
Nature
432
:
917
921
.
88
Devireddy
,
L. R.
,
D. O.
Hart
,
D. H.
Goetz
,
M. R.
Green
.
2010
.
A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production.
Cell
141
:
1006
1017
.
89
Bao
,
G.
,
M.
Clifton
,
T. M.
Hoette
,
K.
Mori
,
S. X.
Deng
,
A.
Qiu
,
M.
Viltard
,
D.
Williams
,
N.
Paragas
,
T.
Leete
, et al
.
2010
.
Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complex.
Nat. Chem. Biol.
6
:
602
609
.
90
Berger
,
T.
,
A.
Togawa
,
G. S.
Duncan
,
A. J.
Elia
,
A.
You-Ten
,
A.
Wakeham
,
H. E.
Fong
,
C. C.
Cheung
,
T. W.
Mak
.
2006
.
Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury.
Proc. Natl. Acad. Sci. USA
103
:
1834
1839
.
91
Zhao
,
H.
,
A.
Konishi
,
Y.
Fujita
,
M.
Yagi
,
K.
Ohata
,
T.
Aoshi
,
S.
Itagaki
,
S.
Sato
,
H.
Narita
,
N. H.
Abdelgelil
, et al
.
2012
.
Lipocalin 2 bolsters innate and adaptive immune responses to blood-stage malaria infection by reinforcing host iron metabolism.
Cell Host Microbe
12
:
705
716
.
92
Fischbach
,
M. A.
,
H.
Lin
,
L.
Zhou
,
Y.
Yu
,
R. J.
Abergel
,
D. R.
Liu
,
K. N.
Raymond
,
B. L.
Wanner
,
R. K.
Strong
,
C. T.
Walsh
, et al
.
2006
.
The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2.
Proc. Natl. Acad. Sci. USA
103
:
16502
16507
.
93
Abergel
,
R. J.
,
M. K.
Wilson
,
J. E.
Arceneaux
,
T. M.
Hoette
,
R. K.
Strong
,
B. R.
Byers
,
K. N.
Raymond
.
2006
.
Anthrax pathogen evades the mammalian immune system through stealth siderophore production.
Proc. Natl. Acad. Sci. USA
103
:
18499
18503
.
94
Raffatellu
,
M.
,
M. D.
George
,
Y.
Akiyama
,
M. J.
Hornsby
,
S. P.
Nuccio
,
T. A.
Paixao
,
B. P.
Butler
,
H.
Chu
,
R. L.
Santos
,
T.
Berger
, et al
.
2009
.
Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine.
Cell Host Microbe
5
:
476
486
.
95
Bachman
,
M. A.
,
S.
Lenio
,
L.
Schmidt
,
J. E.
Oyler
,
J. N.
Weiser
.
2012
.
Interaction of lipocalin 2, transferrin, and siderophores determines the replicative niche of Klebsiella pneumoniae during pneumonia.
MBio
3
:
e00224-11
.
96
Koczura
,
R.
,
A.
Kaznowski
.
2003
.
Occurrence of the Yersinia high-pathogenicity island and iron uptake systems in clinical isolates of Klebsiella pneumoniae.
Microb. Pathog.
35
:
197
202
.
97
Garcia
,
E. C.
,
A. R.
Brumbaugh
,
H. L.
Mobley
.
2011
.
Redundancy and specificity of Escherichia coli iron acquisition systems during urinary tract infection.
Infect. Immun.
79
:
1225
1235
.
98
Recalcati
,
S.
,
M.
Locati
,
A.
Marini
,
P.
Santambrogio
,
F.
Zaninotto
,
M.
De Pizzol
,
L.
Zammataro
,
D.
Girelli
,
G.
Cairo
.
2010
.
Differential regulation of iron homeostasis during human macrophage polarized activation.
Eur. J. Immunol.
40
:
824
835
.
99
Recalcati
,
S.
,
M.
Locati
,
E.
Gammella
,
P.
Invernizzi
,
G.
Cairo
.
2012
.
Iron levels in polarized macrophages: regulation of immunity and autoimmunity.
Autoimmun. Rev.
11
:
883
889
.
100
Kohyama
,
M.
,
W.
Ise
,
B. T.
Edelson
,
P. R.
Wilker
,
K.
Hildner
,
C.
Mejia
,
W. A.
Frazier
,
T. L.
Murphy
,
K. M.
Murphy
.
2009
.
Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis.
Nature
457
:
318
321
.
101
Haldar
,
M.
,
M.
Kohyama
,
A. Y. L.
So
,
W.
Kc
,
X.
Wu
,
C. G.
Briseño
,
A. T.
Satpathy
,
N. M.
Kretzer
,
H.
Arase
,
N. S.
Rajasekaran
, et al
.
2014
.
Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages.
Cell
156
:
1223
1234
.
102
White
,
C.
,
X.
Yuan
,
P. J.
Schmidt
,
E.
Bresciani
,
T. K.
Samuel
,
D.
Campagna
,
C.
Hall
,
K.
Bishop
,
M. L.
Calicchio
,
A.
Lapierre
, et al
.
2013
.
HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis.
Cell Metab.
17
:
261
270
.
103
Donovan
,
A.
,
C. A.
Lima
,
J. L.
Pinkus
,
G. S.
Pinkus
,
L. I.
Zon
,
S.
Robine
,
N. C.
Andrews
.
2005
.
The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis.
Cell Metab.
1
:
191
200
.
104
Abboud
,
S.
,
D. J.
Haile
.
2000
.
A novel mammalian iron-regulated protein involved in intracellular iron metabolism.
J. Biol. Chem.
275
:
19906
19912
.
105
Frazer
,
D. M.
,
G. J.
Anderson
.
2014
.
The regulation of iron transport.
Biofactors
40
:
206
214
.
106
Kristiansen
,
M.
,
J. H.
Graversen
,
C.
Jacobsen
,
O.
Sonne
,
H. J.
Hoffman
,
S. K.
Law
,
S. K.
Moestrup
.
2001
.
Identification of the haemoglobin scavenger receptor.
Nature
409
:
198
201
.
107
Okuda
,
M.
,
R.
Tokunaga
,
S.
Taketani
.
1992
.
Expression of haptoglobin receptors in human hepatoma cells.
Biochim. Biophys. Acta
1136
:
143
149
.
108
Mollan
,
T. L.
,
Y.
Jia
,
S.
Banerjee
,
G.
Wu
,
R. T.
Kreulen
,
A. L.
Tsai
,
J. S.
Olson
,
A. L.
Crumbliss
,
A. I.
Alayash
.
2014
.
Redox properties of human hemoglobin in complex with fractionated dimeric and polymeric human haptoglobin.
Free Radic. Biol. Med.
69
:
265
277
.
109
Tolosano
,
E.
,
S.
Fagoonee
,
E.
Hirsch
,
F. G.
Berger
,
H.
Baumann
,
L.
Silengo
,
F.
Altruda
.
2002
.
Enhanced splenomegaly and severe liver inflammation in haptoglobin/hemopexin double-null mice after acute hemolysis.
Blood
100
:
4201
4208
.
110
Andersen
,
C. B.
,
M.
Torvund-Jensen
,
M. J.
Nielsen
,
C. L.
de Oliveira
,
H. P.
Hersleth
,
N. H.
Andersen
,
J. S.
Pedersen
,
G. R.
Andersen
,
S. K.
Moestrup
.
2012
.
Structure of the haptoglobin–haemoglobin complex.
Nature
489
:
456
459
.
111
Adams
,
P. A.
,
M. C.
Berman
.
1980
.
Kinetics and mechanism of the interaction between human serum albumin and monomeric haemin.
Biochem. J.
191
:
95
102
.
112
Noyer
,
C. M.
,
S.
Immenschuh
,
H. H.
Liem
,
U.
Muller-Eberhard
,
A. W.
Wolkoff
.
1998
.
Initial heme uptake from albumin by short-term cultured rat hepatocytes is mediated by a transport mechanism differing from that of other organic anions.
Hepatology
28
:
150
155
.
113
Hvidberg
,
V.
,
M. B.
Maniecki
,
C.
Jacobsen
,
P.
Højrup
,
H. J.
Møller
,
S. K.
Moestrup
.
2005
.
Identification of the receptor scavenging hemopexin-heme complexes.
Blood
106
:
2572
2579
.
114
Martins
,
R.
,
J.
Maier
,
A. D.
Gorki
,
K. V.
Huber
,
O.
Sharif
,
P.
Starkl
,
S.
Saluzzo
,
F.
Quattrone
,
R.
Gawish
,
K.
Lakovits
, et al
.
2016
.
Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions.
Nat. Immunol.
17
:
1361
1372
.

The authors have no financial conflicts of interest.