Iron Loading and Disease Surveillance.

Iron is an oxidant as well as a nutrient for invading microbial and neoplastic cells. Excessive iron in specific tissues and cells (iron loading) promotes development of infection, neoplasia, cardiomyopathy, arthropathy, and various endocrine and possibly neurodegenerative disorders. To contain and detoxify the metal, hosts have evolved an iron withholding defense system, but the system can be compromised by numerous factors. An array of behavioral, medical, and immunologic methods are in place or in development to strengthen iron withholding. Routine screening for iron loading could provide valuable information in epidemiologic, diagnostic, prophylactic, and therapeutic studies of emerging infectious diseases.

Excessive iron in specific tissues (iron loading) promotes infection, neoplasia, cardiomyopathy, arthropathy, and a profusion of endocrine and possibly neurodegenerative disorders (1-5). An array of behavioral, medical, and immuno methods are being developed to decrease iron loading or its detrimental effects. Routine screening for iron loading in populations exposed to certain diseases can provide valuable epidemiologic, diagnostic, prophylactic, and therapeutic information.

Hazards of Iron Loading

Iron can contribute to disease development in several ways. Excessive amounts [ILLEGIBLE TEXT] metal in specific tissues and cells can hinder the ability of proteins, such as [ILLEGIBLE TEXT] and ferritin, to prevent accretion of free iron. Moreover, in infectious diseases, inflammatory diseases, and illnesses that involve ischemia and reperfusion, iron causes reactions that produce superoxide radicals (6). Nonprotein bound ferric [ILLEGIBLE TEXT] are reduced by superoxide, and the ferrous product is reoxidized by peroxide to regenerate ferric ions and yield hydroxyl radicals, which attack all classes of [ILLEGIBLE TEXT] macromolecules. Hydroxyl radicals can depolymerize polysaccharides, cause [ILLEGIBLE TEXT] strand breaks, inactivate enzymes, and initiate lipid peroxidation (6).

Iron can also increase disease risk by functioning as a readily available essential nutrient for invading microbial and neoplastic cells. To survive and replicate in [ILLEGIBLE TEXT] microbial pathogens must acquire host iron. Highly virulent strains possess exceptionally powerful mechanisms for obtaining host iron from healthy hosts (7 persons whose tissues and cells contain excessive iron, pathogens can much [ILLEGIBLE TEXT] readily procure iron from molecules of transferrin that are elevated in iron [ILLEGIBLE TEXT] In such cases, even microbial strains that are not ordinarily dangerous can cause illness. Markedly invasive neoplastic cell strains can glean host iron more easily less malignant strains or normal host cells (3). Moreover, iron-loaded tissues are especially susceptible to growth of malignant cells (Table 1).

Table 1. Iron loading in specific tissues increased risk for disease

Tissue type        Disease

Alveolar           Pulmonary neoplasi
macrophages        and infection

Anterior           Gonadal and growth
pituitary          dysfunction

Aorta; carotid     Atherosclerosis
and coronary
arteries

Colorectal         Adenoma, carcino
mucosa

Heart              Arrhythmia,
                   cardiomyopathy

Infant             Botulism, salmonel
intestine          sudden death

Joints             Arthropathy

Liver              Viral hepatitis, cirr
                   carcinoma

Macrophages        Intracellular infecti

Pancreas           Acinar and beta cell
                   necrosis, carcinom

Plasma and lymph   Extracellular infecti
Skeletal system    Osteoporosis

Skin               Leprosy, melanoma

Soft tissue        Sarcoma

Substantia nigra   Parkinson's disease

How Microbes Acquire Iron: A Determinant of Host Range and of Tissue Localization

The number of infectious disease agents whose virulence is enhanced by iron continues to increase (Table 2). To obtain host iron, successful pathogens use one or more of four strategies: binding of ferrated siderophilins with extraction of iron at the cell surface; erythrocyte lysis, digestion of hemoglobin, and heme assimilation; use of siderophores that withdraw iron from transferrin; and procurement of host intracellular iron.

Table 2. Microbial genera with strains whose growth in body fluids, cells, tissues, and intact vertebrate hosts is stimulated by excess iron (8)

                                 Gram-positive
                                 and
Fungi              Protozoa      acid-fast bacteria

Candida            Entamoeba     Bacillus
Cryptococcus       Leishmania    Clostridium
Histoplasma        Naegleria     Corynebacterium
Paracoccidioides   Plasmodium    Erysipelothrix
Pneumocystis       Toxoplasma    Listeria
Pythium            Trypanosoma   Mycobacterium
Rhizopus                         Staphylococcus
Trichosporon                     Streptococcus

   Gram-negative bacteri

Acinetobacter    Klebsiell
Aeromonas        Legionell
Alcaligenes      Moraxell
Campylobacter    Neisseria
Capnocytophaga   Pasteurel
Chlamydia        Proteus
Ehrlichia        Pseudom
Enterobacter     Salmonel
Escherichia      Shigella

Microbial strains that use siderophilin binding often have a very narrow host range (7). Bacterial receptors recognize siderophilins generally from a single or closely related host species. Strains of Haemophilus somnus, for example, form receptors for bovine but not for human transferrin; these bacteria are virulent for cattle but not for humans (9). The human pathogen, Neisseria meningitidis, can bind ferrated transferrins from humans and such hominids as chimpanzees, gorillas, and orangutans, but not from [ILLEGIBLE TEXT] nonprimate mammals (10,11). Actinobacillus pleuropneumoniae synthesizes a [ILLEGIBLE TEXT] specific transferrin receptor and causes pneumonia only in hogs (12).

Each of the above three pathogens, as well as other organisms that use [ILLEGIBLE TEXT] binding, can often obtain iron from heme. Helicobacter pylori, for instance, first obtains iron from human ferrated lactoferrin in the gastric lumen. Then, as it [ILLEGIBLE TEXT] into intercellular junctions of epithelial cells in the gastric wall, its sole source of is heme. This pathogen binds neither bovine ferrated lactoferrin nor human, boviequine ferrated transferrin (13).

However, not every pathogen that uses siderophilin binding has a narrow host [ILLEGIBLE TEXT] For example, Staphylococcus aureus can be virulent for a variety of mammalian species. Strains of this organism can bind human, rat, and rabbit transferrins and, much less efficiently, bovine, porcine, and avian transferrins (14). Moreover, [ILLEGIBLE TEXT] of S. aureus also may produce siderophores (15,16). These small molecules can withdraw iron from transferrins synthesized by a variety of host species. The siderophore, staphyloferrin A, removes iron from both human and porcine [ILLEGIBLE TEXT] thus, the metal can be available to invading cells in humans and in hogs. Erythrolysis, digestion of hemoglobin, and heme assimilation are available to strains of aureus. Bacterial hemolysins generally are active against erythrocytes from sever although not from all, potential host species.

Virulent streptococci are examples of bacteria that neither bind siderophilins [ILLEGIBLE TEXT] produce siderophores yet proficiently invade and replicate in many tissues in [ILLEGIBLE TEXT] host species. The cellulytic activities of these pathogens enable them to access [ILLEGIBLE TEXT] intracellular sources of host iron as hemoglobin, myoglobin, catalase, and ferritin (17).

The remarkable versatility for host species shown by Listeria monocytogenes illustrates the adeptness of this organism in procuring iron. Although mainly a saprophyte that lives in the plant-soil environment, L. monocytogenes can be [ILLEGIBLE TEXT] by humans and other mammals through ingestion of undercooked tissue of other mammals, birds, fish, and Crustacea, as well as from raw vegetables. Unable to [ILLEGIBLE TEXT] siderophilins or form siderophores, L. monocytogenes obtains iron by using [ILLEGIBLE TEXT] exogenous siderophores of other microorganisms or natural catechols, such as dopamine and norepinephrine, in host tissues. The pathogen expresses a cell surf ferric reductase that recognizes the siderophoric chelated iron site; the metal is [ILLEGIBLE TEXT] reduced and assimilated (18). Furthermore, in contrast to saprophytic strains, [ILLEGIBLE TEXT] pathogenic strains of L. monocytogenes are hemolytic.

To grow within host cells, pathogens apparently are not required to synthesize siderophilin binding sites or form siderophores. For instance, unlike the wild [ILLEGIBLE TEXT] siderophore-minus mutants of Salmonella Typhimurium cannot grow in [ILLEGIBLE TEXT] compartments of the host. However, both the wild and mutant strains replicate [ILLEGIBLE TEXT] host cells (19). Possible sources of intracellular iron are heme, iron released from transferrin at pH 5.5-6, and ferritin.

For at least two pathogens, Francisella tularensis and Legionella pneumophila, [ILLEGIBLE TEXT] host intracellular niche is obligatory. Like the mutant strain of S. Typhimurium, [ILLEGIBLE TEXT] organisms are unable to access iron in extracellular fluids and tissues. Culturing [ILLEGIBLE TEXT] bacteria in laboratory media requires markedly elevated concentrations of iron (20,21).

In host intracellular niches, growth of microbial pathogens is stimulated by [ILLEGIBLE TEXT] and depressed by decrease of iron. Indeed, at least one bacterial pathogen, Ehrlic chaffeensis, induces elevation of iron in its host cells; intracellular inclusions of [ILLEGIBLE TEXT] organism cause the host cell to upregulate expression of the transferrin receptor mRNA (22).

Iron Withholding Defense System

Hosts use several mechanisms (Table 3) to withhold iron from invading [ILLEGIBLE TEXT] neoplastic cells: stationing of potent iron binding proteins at sites of impending microbial invasion; lowering iron levels in body fluids, diseased tissues, and [ILLEGIBLE TEXT] cells during invasion; and synthesizing immunoglobulins to the iron acquisition antigens of microbes.

Table 3. The iron withholding defense system (1,8)

Constitutive components
  Siderophilins

      Transferrin in plasma, lymph, cerebrospinal fluid

      Lactoferrin in secretions of lachrymal and mammary glands
      and of respiratory, gastrointestinal, and genital tracts

  Ferritin within host cells

Processes induced at time of invasion
  Suppression of assimilation of 80% of dietary iron(a)

  Suppression of iron efflux from macrophages that have digested
  effete erythrocytes to result in 70% reduction in plasma iron(a)

  Increased synthesis of ferritin to sequester withheld iron(a)

  Release of neutrophils from bone marrow into circulation and then
  into site of infection(a)

  Release of apolactoferrin from neutrophil granules followed by
  binding of iron in septic sites

  Macrophage scavenging of ferrated lactoferrin in areas of sepsis
  and of tumor cell clusters

  Hepatic release of haptoglobin and hemopexin (to bind extravasated
  hemoglobin and hemin, respectively)

  Synthesis of nitric oxide (from L-arginine) by macrophages to
  disrupt iron metabolism of invaders(b)

  Suppression of growth of microbial cells within macrophages via
  downshift of expression of transferrin receptors and enhanced
  synthesis of Nrampl (23) by the host cells(b)

  Induction in B lymphocytes of synthesis of immunoglobulins to
  iron-repressible cell surface proteins that bine either heme,
  ferrated siderophilins, or ferrated siderophores

(a) Activated by interleukin-1 or -6 or by tumor necrosis factor-[square].

(b) Activated by interferon-g.

High concentrations of iron not only benefit invading cells, they may also [ILLEGIBLE TEXT] antimicrobial activities of defense cells. In in vitro studies, 150 [micro]M iron [ILLEGIBLE TEXT] macrophage killing of Brucella abortus (24) and, without altering phagocytosis, [micro]M iron enhanced anti-Candida activity of microglia (25). In the latter system, [ILLEGIBLE TEXT] metal suppressed synthesis of nitric oxide but not of tumor necrosis factor A. By generating oxidant-sensitive mediators, iron may focus influx of neutrophils to [ILLEGIBLE TEXT] of infection (26). Iron loading of staphylococci increased their killing by [ILLEGIBLE TEXT] macrophages, and neutrophil-derived cytoplasts but not by neutrophils (27). [ILLEGIBLE TEXT] conditions can impair iron withholding (Table 4); numerous studies have present evidence that risk for infection or neoplasia is increased significantly in persons these conditions.

Table 4. Conditions that can compromise iron withholding (1,3)

Excessive intake of iron through intestinal absorption
  Behavioral and nutritional factors

    Accidental ingestion of iron tablets

    Adulteration of processed foods with inorganic
    iron or blood

    Excessive consumption of red meats
    (heme iron)

    Excessive intake of alcohol (HCl secretion
    enhanced)

    Folic acid deficiency

    Ingestion of ascorbic acid with inorganic iron

    Use of iron cookware

  Genetic and physiological factors

    African siderosis

    Asplenia (mechanism unknown)

    Pancreatic deficiency of bicarbonate ions

    Porphyria cutanea tarda

    Regulatory defect in mucosal cells in
    hemochromatosis

    Thalassemia, sicklemia, other
    hemoglobinopathies

  Parenteral iron
    Intramuscular and intravenous iron saccharate
    injections in excess

    Multiple transfusions of whole blood or
    erythrocytes in excess

  Inhaled iron
    Exposure to amosite, crocidolite, or tremolite
    asbestos

    Exposure to urban air particulates

    Mining iron ore, welding, grinding steel

    Painting with iron oxide powder

    Tobacco smoking (1-2 [micro]g iron inhaled per
    cigarette pack)

  Release of body iron from compartments into plasma
    Efflux of erythrocyte iron in hemolytic diseases

    Efflux of hepatocyte iron in hepatitis

  Deficit in iron withholding
    Transferrin

    Decreased synthesis

      Congenital defect

      Lack of dietary amino acids in kwashiorkor or
      in jejunoileal bypass

      Decreased activity in acidosis

    Lactoferrin

      Neutropenia

      Substitution of bovine milk or milk formula for
      human milk in nursing nutrition

    Haptoglobin

      Decreased synthesis in persons with haplotype
      2-2 (28)

[ILLEGIBLE TEXT] apparently independent of inflammation, is significantly reduced in persons with levels of iron (5).

Strengthening the Iron Withholding Defense

A considerable array of behavioral, medical, and immunologic methods are in [ILLEGIBLE TEXT] or in development for strengthening iron withholding (Table 5) (3). Additional precautions are indicated for persons who are known to be (or have a tendency to become) iron loaded. For example, persons with elevated iron due to either hemochromatosis or alcoholism are cautioned to avoid eating raw oysters, which contain Vibrio vulnificus (30). Another pathogen that likewise causes severe [ILLEGIBLE TEXT] infection in hosts with elevated iron is Capnocytophaga canimorsis. Accordingly persons who have hemochromatosis, alcoholism, or asplenia are advised to [ILLEGIBLE TEXT] prompt antibiotic therapy if they are exposed to a dog bite (31).

Table 5. Methods of strengthening the iron withholding defense system

Reduction of excessive intake of ingested iron
  Decreased consumption of red meats (heme iron)

  Avoidance of processed foods that have been adulterated with
  inorganic iron or with blood

  Decreased consumption of alcohol and ascorbic acid

  Elimination of iron supplements unless an iron deficiency has
  been correctly diagnosed

Reduction of excessive intake of parenteral iron
  Inject iron saccharates only if unequivocally justified

  Transfuse blood or erythrocytes only if unequivocally justified

  Substitute erythropoietin (+ minimal amount of iron) for whole
  blood transfusions when possible

Reduction of excessive inhalation of iron
  Eliminate use of tobacco

  Use iron-free chrysotile in place of iron-loaded amosite,
  crocidolite, tremolite varieties of asbestos

  Use mask to avoid inhalation of urban air particulates

  Use mask and protective clothing when mining or cutting
  ferriferous substances

Reduction of iron burden by regular depletion of whole blood or
erythrocytes
  Avoidance of premature hysterectomy

  Routine ingestion of aspirin

  Regular donations of whole blood or erythrocytes

  Vigorous exercise

Increased use of iron chelators
  Use human milk (high in lactoferrin, low in iron) rather than
  milk formula (lacking in lactoferrin, high in iron) in nursling
  nutrition

  Use tea (iron-binding tannins) and bran (iron-binding phytic
  acid)

  Continue research and development (R&D) of potential iron
  chelator drags (e.g., recombinant human lactoferrin;
  hydroxpyridones; pyridoxal isonicotinoyl hydrazones)

Initiation of prompt therapy of chronic infections and neoplastic
diseases to fores saturation of iron withholding defense system
  Continued R&D of cytokines such as interferon g that induce
  cellular iron withholding

  Continued R&D of passive and active methods of immunization
  against surface receptor proteins used by microbial and
  neoplastic cells to obtain iron

De-ironing by phlebotomy is effective in lowering risk for cardiovascular disease (32,33) and various neoplasms (34), as well as in therapy for hepatitis C (35). Interfering with iron metabolism by administering gallium can be useful in suppressing growth of lymphoma and bladder cancer cells (36). The antineoplast action of monoclonal antibodies against ferrated transferrin receptors has been examined (37). Combinations of the iron chelator, deferoxamine, with gallium or antibodies against ferrated transferrin receptors increase effectiveness against [ILLEGIBLE TEXT] cells.

The natural iron scavenger, lactoferrin, has been shown to remove free iron from synovial fluid aspirated from joints of rheumatoid arthritic patients (38). [ILLEGIBLE TEXT] human lactoferrin, which is indistinguishable from native breast milk lactoferrin respect to its iron binding properties, is now available (39) and could become a [ILLEGIBLE TEXT] useful addition to our array of de-ironing pharmaceutical products.

A recently discovered integral membrane phosphoglycoprotein, Nrampl, is [ILLEGIBLE TEXT] exclusively in macrophages and is localized to phagolysosomes. The protein suppresses replication of intramacrophage microbial invaders apparently by [ILLEGIBLE TEXT] iron availability (23). A second protein, Nramp2, is involved in enhancement of intestinal iron absorption (40). Future research might develop useful medical procedures for modulation of the actions of these proteins.

Potential vaccines that incorporate iron acquisition antigens of pathogens in the families Neisseriaceae and Pasteurellaceae are being developed by several [ILLEGIBLE TEXT] groups. For example, in Moraxella catarrhalis, the recombinant transferrin [ILLEGIBLE TEXT] protein B (TbpB) has been shown to elicit bactericidal antibodies (41) In N. meningitidis, antisera to TbpA and TbpB were bactericidal for both homologous heterologous strains (42,43). Because the antigenic proteins function at the cell surfaces of the pathogens, the receptors are potentially ideal vaccine candidates. synthesis of the receptors, the organisms must be cultured in iron-restricted [ILLEGIBLE TEXT]

Perspectives and Conclusions

There is growing awareness that transmissible agents are involved in diseases no earlier suspected of being infectious (44-46). A recent review contains a list of 3 degenerative, inflammatory, and neoplastic diseases associated in various ways specific infectious agents (44). Other chronic inflammatory diseases, such as sarcoidosis, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, Wegener granulomatosis, diabetes mellitus, primary biliary [ILLEGIBLE TEXT] tropical spree, and Kawasaki disease may also have infectious etiologies (45). Excessive iron is correlated with synovial damage in rheumatoid arthritis (47) an with impaired glucose metabolism in diabetes (48). The association of Chlamydi pneumoniae (49) and excessive iron (5) with cardiovascular disease is well established. Growth of this pathogen is strongly suppressed by iron restriction (5

Proving the role of infection in chronic inflammatory diseases and cancer present challenges (46). The means by which pathogens suppress, subvert, or evade host defenses to establish chronic or latent infection have received little attention. However, the association and causal role of infectious agents in chronic [ILLEGIBLE TEXT] diseases and cancer have major implications for public health, treatment, and prevention (44-46).

Iron loading is a risk factor in these illnesses, as well as in classic infectious [ILLEGIBLE TEXT] Because the prevalence of iron loading in various populations can be remarkably high, routine screening of iron values in host populations could provide valuable information in epidemiologic, diagnostic, prophylactic, and therapeutic studies [ILLEGIBLE TEXT] emerging infectious diseases.

Acknowledgment

Dedicated to Jerome L. Sullivan, pioneer and leader in our awareness of the role of iron in cardiovascular disease.

Support for this review was provided by the Office of Research and the University Graduate School, Indiana University, Bloomington, IN, USA.

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Emerging Infectious Diseases Journal National Center for Infectious Diseases Centers for Disease Control and Prevention

URL: http://www.cdc.gov/ncidod/eid/vol5no3/weinberg.htm

Dr. Weinberg is professor emeritus of microbiology in both the College of Arts and Sciences the School of Medicine at Indiana University, Bloomington, IN. His studies on iron were initiate 1952. Since retiring from teaching in 1992, he has devoted full time to research.

Address for correspondence: E.D. Weinberg, Jordan Hall 142, Indiana University, Blooming IN 47405, USA; fax: [phone]; e-mail: [e-mail].