888
Iron, Infections, and Anemia of Inflammation
Rafael L. Jurado
From the Department of Medicine, Emory University School of
Medicine, Atlanta, and the Department of Veterans Affairs Medical
Center (Atlanta), Decatur, Georgia
Iron is essential to all microorganisms. To obtain iron from the very low concentrations present
in their environment, microorganisms have developed sophisticated mechanisms such as the siderophore system. As a primitive defense mechanism, humans have developed mechanisms to withhold
iron from microorganisms. Iron-binding proteins such as transferrin, ferritin, and lactoferrin have
a central role in human ferrokinetics. These iron-binding proteins also participate in the process of
decreasing iron availability for the microorganisms. They do so by decreasing iron reutilization.
Anemia of inflammation (previously called anemia of chronic disease) is seen in the setting of
infectious, inflammatory, and neoplastic diseases. It results, in part, from changes in the intracellular
metabolism of iron. Alterations of iron physiology seen in many clinical circumstances make excess
iron available to microorganisms, thus enhancing their pathogenicity. Understanding the molecular
basis of iron withholding by the human host, both in the absence of and during infection, and that
of iron acquisition by microorganisms may provide us with new and innovative antimicrobial agents
and vaccines.
Iron is vital for microorganisms [1 – 3]. There is abundant
iron in the human body, most of which is bound to hemoglobin,
myoglobin, and the cytochromes. Most of the iron that is not
integrated to these essential proteins is bound to the iron-binding proteins (transferrin, lactoferrin, and ferritin). These ironwithholding mechanisms make the amount of iron available to
bacteria extremely small, on the order of 10015M. Because the
iron requirements of microorganisms are on the order of 1006M,
as an evolutionary response, they have developed different
mechanisms to obtain it. The human host uses iron withholding
as a form of nonspecific immunity to discourage infection, and
this sequestration is involved in the pathogenesis of anemia of
inflammation (AoI). When excess iron becomes available under
certain clinical circumstances (e.g., hemolysis, trauma, hemochromatosis, the use of desferrioxamine, iron supplementation,
or transfusions), it becomes possible for certain microorganisms to proliferate and cause disease.
Iron Needs of Microorganisms
The fact that microorganisms can multiply in vivo and cause
infections despite the virtual absence of freely available iron
in body fluids suggests that they have the capacity to adapt
to the iron-restricted environment by the development of sophisticated mechanisms to overcome iron scarcity. The most
important of these adaptive mechanisms is the siderophore system. Microorganisms have developed high-affinity iron-bind-
ing compounds known as siderophores (Greek for ‘‘iron bearers’’) [3]. Siderophores are low-molecular-weight (õ1,000),
virtually ferric-specific ligands whose function is to scavenge
iron for microorganisms. Siderophore synthesis is inversely
related to the amount of iron in the environment and is under
tight control of an operon [4]. Besides the siderophore system,
microorganisms have other mechanisms for the acquisition of
iron: enzymatic breakdown of iron-binding proteins [5], reduction of the Fe3/ complex to the Fe2/ complex (leading to
release of iron [6]), and interaction of receptors present on the
microbial surface with the Fe-glycoprotein complex [7].
Mechanisms Developed by the Host to Deprive
Microorganisms of Iron
Iron withholding is mediated by a series of iron-binding
proteins: ovoalbumin, transferrin, lactoferrin, and ferritin [8].
The binding and saturation characteristics of these iron-binding
proteins result in concentrations of free iron on the order of
10015M. Moreover, under normal circumstances, there is an
excess of unoccupied binding sites in plasma transferrin, which
are capable of binding extra iron. This extra iron-binding capacity will serve to keep levels of free iron constant during periods
of rapid entry of the metal into the circulation.
Ovoalbumin
Received 8 November 1996; revised 19 March 1997.
Reprints or correspondence: Dr. Rafael L. Jurado, Department of Veterans
Affairs Medical Center (Atlanta), 1670 Clairmont Road, Decatur, Georgia
30033.
Clinical Infectious Diseases 1997;25:888–95
This article is in the public domain.
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09-19-97 08:26:31
Ovoalbumin (conalbumin) was the first protein discovered
that suggested an important role for iron in host defense mechanisms. The first observations of the antibacterial properties of
iron-binding proteins were made rather serendipitously by
Shade and Carolin [9] in 1944.
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Iron and Infection
Transferrin
Schade and Caroline [10] reasoned that an iron-binding protein with functions similar to that of conalbumin must be present in humans. They demonstrated such a protein, initially
called siderophilin, and showed its antimicrobial capacity in
human serum. Later on, Holmberg and Laurell [11] suggested
the name transferrin. Transferrin’s affinity for iron is pHdependent (the lower the pH the lower the affinity). This binding characteristic of transferrin has been implicated in the
pathogenesis of rhinocerebral mucormycosis in patients with
diabetic ketoacidosis [12, 13], in whom acidemia increases
free iron (by decreasing transferrin’s binding affinity). The
zygomycete will use this excess iron to its advantage, leading
to invasive rhinocerebral mucormycosis. Lambert and Hunter
[14] demonstrated the role of unsaturated transferrin as a predictor of survival in cases of pneumococcal infections.
Lactoferrin
Lactoferrin is a 78-kD cationic protein present in mammalian
milk (where it was originally identified, hence the name), certain mucosal secretions, and polymorphonuclear (PMN) leukocytes (where it is a component of the specific [secondary]
granules). Using sonicated extracts of rabbit PMN leukocytes,
Bullen and Wallis [15] found that lactoferrin present in PMN
leukocytes was 14% – 40% saturated with iron. Thus, lactoferrin
has the capacity to bind relatively large amounts of free iron.
Lactoferrin synthesis and release from the secondary granules
is increased by IL-1, as part of the acute-phase reaction (APR)
[16]. Release of apolactoferrin (iron-free lactoferrin) by PMN
leukocytes into an area of bacterial growth leads to its in situ
combination with iron.
In contrast to conalbumin and transferrin, lactoferrin’s affinity for iron increases as pH decreases. Thus, lactoferrin is an
efficient iron scavenger and/or trap at sites of infection or
inflammation, where the pH has been lowered by the release
of lactic acid and other by-products of the leukocytes and/
or microbial metabolism. Several reports have attested to the
importance of lactoferrin in host defenses by showing that
patients with lactoferrin-deficient PMN leukocytes have an increased susceptibility to infections [17 – 20].
Two facts contribute to lactoferrin’s efficiency in iron sequestration in the reticuloendothelial system. First, because of
its higher affinity for iron at lower than physiological pH,
lactoferrin binds more iron than transferrin at sites of inflammation. Second, lactoferrin receptors, while present on the surface of macrophages, are not expressed on the surface of erythroid precursors. During the APR, the macrophages become
activated. Activated macrophages exhibit an increase in the
concentration of lactoferrin receptors on their surface, which
further increases the internalization of iron (keeping it away
from the microorganisms and the erythroid precursors). Thus,
lactoferrin-bound iron is taken up by macrophages in prefer-
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889
ence to erythroid precursors. Within the macrophage, the lactoferrin-bound iron is transferred to the iron-storage molecule
ferritin (vide infra), which traps it in a more stable form. Besides its role in iron withholding, lactoferrin has an intrinsic
bactericidal capacity [21].
Ferritin
Although seldom saturated, a ferritin molecule can store up
to 4,500 iron atoms. Under basal conditions, iron stores closely
regulate the synthesis of ferritin. During inflammation, ferritin
synthesis is increased under the influence of IL-1 and TNF [22,
23]. Cytokines can also induce ferritin synthesis indirectly by
increasing iron uptake by hepatocytes. An expanded intracellular pool of iron in turn stimulates ferritin synthesis [24]. Following turpentine-induced inflammation, increased ferritin synthesis precedes the decrease in serum iron. Maximal reduction in
serum iron occurs after 12 hours of inflammation [25]. Thus,
both increased lactoferrin delivery of iron to macrophages and
increased ferritin synthesis play central roles in the sequestration of iron as part of the pathogenesis of AoI (see below).
AoI
AoI became a nosologic entity following the seminal article
by Cartwright and Wintrobe [26]. It is a very common type of
anemia [27]. I agree with Schilling [28] that we should abandon
the misnomer ‘‘anemia of chronic disease’’ and replace it with
AoI, which better reflects our growing understanding of its
pathogenesis. AoI is usually mild, with hematocrits ranging
between 30% and 40% and hemoglobin levels of 9 – 13 g/dL.
Nonetheless, in about 20% of cases, the hematocrit may drop
below 25% [29]. A pathological process, such as chronic infections, inflammatory infections, or neoplastic diseases, is usually
present at the time of detection of AoI. The underlying problem
is usually easily identified. Occasionally, AoI is the first manifestation of such an underlying disease. The word chronic may
also be misleading, because changes in hemoglobin levels and
hematocrit can occur in õ2 weeks [30].
Pathogenesis of AoI
AoI is a multifactorial and complex process [31, 32] whose
many steps are mediated by cytokines such as IL-1, TNF, and
IFN. Increased plasma concentrations of these cytokines have
been described in patients with disorders associated with AoI
[33 – 36]. In addition, the therapeutic administration of recombinant human TNF and IFN to patients has been reported to
produce anemia [37, 38]. AoI is mainly the result of decreased
RBC production secondary to decreased iron availability and
erythropoietin (EPO) dysfunction.
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lization, thereby underscoring the importance of the macrophage storage capacity in the pathogenesis of AoI.
Decreased iron absorption. Decreased iron absorption
plays only a minor role in hypoferremia in patients with AoI.
Transferrin may play a role in these changes in iron absorption.
Once synthesized in the liver, apotransferrin is secreted in bile
into the gastrointestinal tract lumen. In the lumen, it binds iron
and delivers it to the transferrin receptor located in the brush
border of the mucosal cell [45]. Because transferrin synthesis
is decreased during the APR, interference with iron absorption
at this step may explain the decreased iron absorption in patients with chronic inflammation.
Alterations in EPO Metabolism
Figure 1. The iron compartments of the reticuloendothelial system
(RES) macrophage are the labile pool of iron and the storage pool
(see text). The RES macrophage can uptake iron in two forms: phagocytosis of effete RBCs (main source) and internalization of transferrinbound iron (through transferrin receptors). Compartment A represents
the labile pool of iron, which can be either further stored in compartment B or recirculated to transferrin for erythropoiesis. The storage
pool is made up of ferritin (early release storage) and hemosiderin
(late release storage).
Decreased Iron Availability
Decreased iron availability is due to decreased iron reutilization and decreased iron absorption.
Decreased iron reutilization. In addition to the iron-binding proteins, reticuloendothelial macrophages play a central
role in decreased iron reutilization. As part of the APR, macrophages increase their lactoferrin receptors, thereby enabling
them to internalize more lactoferrin-bound iron. Iron released
from the reticuloendothelial macrophage is reduced by inflammation [39, 40]. In patients with inflammatory conditions,
ferritin synthesis is increased in the activated reticuloendothelial cells [41, 42]. This increase in ferritin synthesis precedes
hypoferremia [25], thus suggesting that increased iron binding
by ferritin may be the mechanism responsible for the reduction
in iron output from the reticuloendothelial cell.
Iron kinetic studies have demonstrated the existence of a
small labile pool of iron (compartment A in figure 1) with a
rapid turnover rate [43, 44]. The iron in this labile pool is
either released into the blood or transferred to a storage pool
(compartment B figure 1). The size and capacity for iron release
of the labile pool is the same for normal individuals and for
patients with anemia secondary to rheumatoid arthritis. The
storage pool, however, is greatly expanded in patients with
rheumatoid arthritis. Thus, an increase in the storage pool will
lead to iron withholding and play a central role in iron underuti-
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There are data suggesting that EPO disturbances are a central
component of the pathogenesis of AoI.
Decreased EPO synthesis. EPO release in response to anemia is blunted in patients with AoI [46]. This subnormal response may be the result of the action of several cytokines
[47]. Serum and urine EPO levels are lower than expected for
the level of anemia in patients with AoI [48 – 53].
Impaired EPO action. Hematocrit rises in response to EPO
in patients with AoI, but the magnitude of the change is subnormal, thus suggesting decreased responsiveness of the erythroid
precursors to EPO. This unresponsiveness may be the result
of macrophage-derived factors [54 – 58].
Decreased RBC survival. RBC survival in patients with
AoI is typically reduced to 60 – 90 days compared with the
normal 90 – 120 days [59, 60]. Probably more important in
decreased RBC life span in patients with AoI is the role of
macrophages in RBC disposal. A normal function of the macrophages is removal of senescent RBCs from the circulation.
Therefore, it is possible that macrophages activated by the
inflammatory process will exaggerate this normal function. Senescent RBCs and those coated by Igs or immune complexes
are cleared more efficiently by an activated phagocytic system
[61]. Although fever per se has been reported to decrease RBC
survival [62], not all patients with AoI are febrile.
Cartwright and Lee [63] speculated that AoI — given that
the anemia is mild and thus of little, if any, deleterious effect
to the host — could represent some appropriate homeostatic
mechanism. I submit that the purpose of AoI is to deprive
invading microorganisms of iron. This possible role of AoI
could be integrated into the concept of ‘‘nutritional immunity’’
(figure 2). Iron withholding in patients with AoI may be construed as a host defense mechanism in that it is an attempt to
deprive the invading microorganisms of iron as a nutrient.
Fever (a component of the APR), independent of cytokineinduced hypoferremia, may also contribute to iron deprivation.
Elevated temperature suppresses the synthesis of siderophores
and their receptors [64, 65]. Thus, fever appears to have two
synergistic effects aimed at decreasing bacterial growth rates:
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Iron and Infection
Figure 2. IL-1 and other cytokines mediate both arms of nutritional
immunity. By mediating fever, they decrease siderophore production
by the bacteria. Through the acute-phase reaction (APR), they participate in the pathogenesis of anemia of inflammation (AoI). Both these
effects lead to bacterial iron deprivation.
891
fever, an acute and severe hemolytic disorder caused by Bartonella bacilliformis (a gram-negative bacterium found almost
exclusively in Peru and Ecuador) [73]. If salmonella bacteremia
occurs during the acute hemolytic phase of bartonellosis, the
prognosis is worse than if it occurs following the abatement
of the hemolytic process, which suggests that hemolysis (with
the consequent increased iron availability) contributes to the
severity of salmonella bacteremia.
‘‘Local’’ hemolysis as a result of trauma (i.e., hematoma
formation) and severe burn-associated hemolysis may contribute to increased susceptibility to infections by increasing the
availability of iron. Hemoglobin present in the peritoneal cavity
may act as a virulence factor in patients with postoperative
peritoneal infections. Experimental data support this contention
[74, 75]. Certain Porphyromonas and Prevotella species can
have access to iron trapped in iron-binding proteins by degrading such proteins as hemoglobin, haptoglobin, hemopexin, and
transferrin [5].
Hemochromatosis and Other Iron Overload States
decreased iron availability (mediated by AoI) and decreased
siderophore production.
Iron Excess and Infections
Different mechanisms may make excess iron available for
microorganisms, and various specific infections appear to thrive
in this environment of excess iron.
Hemolysis
Large amounts of iron can be made available during hemolysis in patients with conditions such as sickle cell crisis [66]
and other hemolytic disorders [67]. Iron thus released is not
only made available for microorganisms but also affects the
mononuclear phagocytic system, one of whose roles is the
clearance of bacteria from the bloodstream [68, 69]. Eaton et al.
[70] demonstrated the antibacterial effects of the hemoglobinhaptoglobin complex by showing that sublethal doses of Escherichia coli become lethal when they are administered together
with hemoglobin to rats but do not become lethal if sufficient
haptoglobin to bind all the hemoglobin is also given to the
animals.
Salmonella infections are seen with increased frequency in
the presence of hemolytic disorders such as malaria and bartonellosis. During the era of malariotherapy for patients with
neurosyphilis, the frequency of salmonella bacteremia was so
high that considerations were given to administering a vaccine
against Salmonella enteritidis infection to these patients [71].
An association between bacteremia due to non-typhi Salmonella species and spontaneous malaria has also been reported
[72]. Salmonella bacteremia occurs in 40% of cases of Oroya
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Hemochromatosis, the epitome of iron overload, is associated with an increased incidence of certain infections. Serum
from patients with hemochromatosis contains a pool of iron
complex not present in healthy individuals from which bacteria
can readily obtain iron [76]. Vibrio vulnificus is one of the
microorganisms seen in association with hemochromatosis. Although this bacterium is usually inhibited by human serum, it
thrives in the presence of 1 mg of hemoglobin/mL, whether or
not it is complexed with haptoglobin [77]. This microbe can
grow rapidly in sera of individuals with hemochromatosis [78].
The growth of V. vulnificus in sera of patients with hemochromatosis can be inhibited by the addition of human apotransferrin. Primary hemochromatosis was present in 50% of cases of
multiple liver abscesses due to Yersinia enterocolitica, and
other forms of iron overload (Bantu siderosis, thalassemia major, and iron therapy) were present in 13% [79]. The incidence
of infections with Yersinia pseudotuberculosis in patients with
hemochromatosis is also increased [80].
Patients with chronic renal failure frequently have multifactorial iron overload. Before the use of EPO, these patients
received multiple transfusions (each unit of whole blood contained 200 mg of iron). These patients also received frequent
parenteral iron preparations. Moreover, one or more alleles
for hemochromatosis may be present that predispose patients
undergoing dialysis to iron overload [81].
It is therefore of interest that 10 episodes of yersinia bacteremia (nine due to Y. enterocolitica and one due to Y. pseudotuberculosis) were detected in a cohort of Belgian patients undergoing dialysis [82]. Before having yersinia bacteremia, the
patients had received a mean dose of parenteral iron { SD of
24.9 { 19.5 g; their mean ferritin concentration { SD was 2.1
{ 2.125 ng/mL, and stained bone marrow specimens from five
patients were strongly positive for iron. Two of these episodes
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occurred within 4 months of the initiation of desferrioxamine
therapy (vide infra). Data on invasive yersinia disease and iron
status were obtained for 1,656 patients undergoing dialysis in
Belgium. Yersinia bacteremia was described in five of 539
individuals with serum ferritin levels of ú500 ng/mL, while
no cases occurred in 882 individuals with serum ferritin levels
of õ500 ng/mL (P õ .05).
Iron Supplementation
Infant botulism differs from foodborne botulism in that the
botulinus toxin is elaborated in vivo (i.e., in the gastrointestinal
tract). There is microbiological evidence [83] and clinical evidence [84] implicating iron as a virulence factor for infant
botulism.
Therapeutic Use of Desferrioxamine
Desferrioxamine is a siderophore produced by Streptomyces
pilosus. It has a high affinity for ferric iron and a greater ironbinding efficiency than transferrin. Desferrioxamine provides
iron to bacteria through mobilization from tissue deposits (the
first step in the elimination of the excess iron burden and an
incidental occurrence when desferrioxamine is being used for
aluminum chelation). Iron is thus made available to microorganisms, which having the capacity through their siderophore
receptors to internalize and utilize it, can increase their growth
and virulence [85, 86].
There are many reports on the increased incidence of certain
types of infections, such as yersinia [82, 87 – 89] and zygomycete [90 – 92] infections, related to the therapeutic use of desferrioxamine. The frequent use of desferrioxamine for treatment
of aluminum toxic effects in patients with chronic renal failure
potentially increases the risk of infection with iron-dependent
organisms. In the setting of renal failure, the half-lives of desferrioxamine and its chelates (ferroxamine and aluminoxamine)
are markedly prolonged, by as much as 10-fold. This alteration
in desferrioxamine pharmacokinetics will allow microorganisms longer periods to utilize the chelated iron. There have
been multiple reports of invasive zygomycosis in patients with
chronic renal failure who are treated with desferrioxamine
[93 – 96]. On the basis of these reports, the use of this agent
for patients with renal failure should be approached with great
caution.
Although the main indications for the use of desferrioxamine
are iron and aluminum overload, it is likely that its therapeutic
indications will extend to such conditions as malignancy and
autoimmune disorders [97]. Thus, the number of patients at
risk for desferrioxamine-associated invasive yersinia infection
and mucormycosis may increase in the near future.
Blood Transfusion
Repeated blood transfusions can lead to iron overload. In
addition to iron overload, transfused blood per se has been
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CID 1997;25 (October)
associated with certain bacterial infections in which free iron
in the stored blood (as a result of in vitro hemolysis) may play
a role. Increased iron availability in the stored blood facilitates
the proliferation of certain microorganisms. In most cases of
transfusion-associated yersinia bacteremia reported in the literature, the involved blood had been stored for ú3 weeks (there
is a linear correlation between duration of storage and extent
of hemolysis) [98]. Besides iron availability, the temperature
at which blood is stored plays a role in the specific organisms
involved. Yersinia and other psychrophilic organisms (such as
Enterobacter agglomerans) grow well at 47C, the temperature
at which blood is stored. Yersinia can multiply to large numbers
in the stored blood without showing visible evidence of contamination, such as microagglutination, turbidity, or overt hemolysis. Yersinia is not commonly found in the environment,
and most cases of transfusion-related yersinia bacteremia appear to be related to asymptomatic or only mildly symptomatic
donors (as evidenced by clinical or serological data) [98, 99].
Diabetic Ketoacidosis
The classical association of mucormycosis (zygomycete)
with diabetic ketoacidosis and other disorders characterized by
acidosis (i.e., renal tubular acidosis) is most likely multifactorial. There is evidence that one of the pathogenetic factors is
increased iron availability secondary to acidosis [12, 13].
Therapeutic Implications of the Role of Iron in Infections
Understanding the molecular basis of iron acquisition by
pathogenic microorganisms has provided new insights that are
potentially useful for the development of innovative therapeutic
measures and alternatives to antibiotic use. One such approach
is the production of antibacterial agents that interfere with the
siderophore – siderophore receptor system. The siderophore enterochelin is produced by a number of pathogenic enterobacteria and could be complexed with ions other than iron (such
as scandium [Sc3/] or indium [In3/]) to yield antimetabolites.
Experimental data suggest this may be a viable approach
[100 – 102]. The use of ferrisiderophore receptors as antigenic
sites for the development of vaccines has also been explored
[103]. Eaton et al. [70] have proposed the use of haptoglobin
in the treatment of potentially fatal infections in which available
hemoglobin may have a role.
Summary
Iron plays a role both in bacterial pathogenicity and in host
defense mechanisms, which has frequently been underestimated. Bacterial pathogenicity is multifactorial, and iron is but
one of its components. Besides the complex role iron plays
directly in microbial biology (as described in this review),
excess iron also leads to decreased phagocytosis and deficient
oxidative metabolism. Furthering our knowledge in this field
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Iron and Infection
may provide us with a better understanding of microbial pathogenicity and lead to some innovative approaches to antimicrobial therapy.
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