Competition for Iron
Iron Metabolism

Author: Gianpiero Pescarmona
Date: 07/01/2008

Description

Among all the nutrients, iron stands out as having a particularly crucial role in mediating host-pathogen interactions.

  • In animals, evidence for this comes from the diversity of their methods of iron sequestration and from their ability to further deprive invading organisms of iron by depleting plasma iron during the APR (acute-phase response).
  • In pathogens, the strongest evidence comes from the high degree of genomic investment in systems for iron acquisition, the vast range of such systems and their very low iron-binding constants which permit them to be effective even in highly iron-depleted environments.

At first sight the suggestion that iron lies at the centre of an eons-long battle between hosts and their pathogens is surprising, since iron is the second most abundant element on the earth's crust. The explanation lies in a combination of the extreme usefulness of the redox potentials of the ferrous (Fe2+)/ferric (Fe3+) switch (which makes it widely used in enzymic and signalling systems), and the fact that most iron exists in a highly insoluble oxidized state (Fe3+).

Both iron excess and deficiency favour infections

Bacterial and protozoarian strategies

Trypanosoma brucei

The transferrin receptor of Trypanosoma brucei is encoded by genes located in different expression sites. The various expression sites encode slightly different transferrin receptors, which differ substantially in their affinity for transferrin of different host species.

The significance of transferrin receptor variation in Trypanosoma brucei 2003

more details...

Papers Transferrin Receptor Trypanosoma brucei

Viral strategies

HIV

HIV inhibits iron efflux from the cell via the Nef protein

Alain Townsend Molecular control of human iron homeostasis, and interactions of HIV with cellular iron metabolism.

Host strategies

  • transferrin
  • haptoglobin
  • ferritin

Acute Phase Proteins function

Haptoglobin binds hemoglobin
Lactoferrin binds iron
Transferrin binds iron
Ferritin segregates iron (ca 1000/1500 atoms x molecule)

Hemopexin binds heme

NRAMP1 (SLC11A1) polymorphism

Iron and infection: effects of host iron status and the iron-regulatory genes haptoglobin and NRAMP1 (SLC11A1) on host-pathogen interactions in tuberculosis and HIV 2006

In this review, we summarize current knowledge on the relationships between iron and two of the leading infectious causes of death in humankind: HIV and TB (tuberculosis). We examine the relationships both in terms of cause (i.e. the question of whether positive or negative perturbations in iron status affect susceptibility to disease and clinical progression), and in terms of effect (i.e. the pathological consequences of infection on iron homoeostasis). We also examine whether variants in host genes may influence these outcomes. At present, the evidence for gene-nutrient interactions is somewhat limited, so we focus on just two candidate genes that have been examined in some detail:

  • the haemoglobin-binding acute-phase protein, Hp (haptoglobin)
  • the divalent-cation transporter from the phagosome membrane of the macrophage NRAMP1 [natural-resistance-associated macrophage protein-1; now known as SLC11A1 (solute carrier family 11, member 1).

Specific infections in which a role for NRAMP1 polymorphism has been demonstrated

Iron and Vaccination

[Changes in the hemogram and in the laboratory parameters indicative of iron metabolism in mild viral infections]. 1993

  • Abstract
    PURPOSE:
    To assess the duration and intensity of the changes appearing in laboratory values related to iron utilisation during viral infection.
    MATERIAL AND METHODS:
    With previous parental consent, 120 eutrophic infants received vaccination with attenuated measles virus or a combination of measles, mumps and rubella viruses as a model of mild viral infection. A number of laboratory tests were performed on day 0 and in two later occasions (4-21, 9-14 or 9-30); these included blood cell counts, ESR, serum iron, total iron binding capacity, transferrin saturation index, free erythrocytic protoporphyrin, serum ferritin, intra-erythrocytic ferritin, direct anti-human globulin test and C-reactive protein. The statistical analyses were done in accordance with ANOVA, Student's t test, Wilcoxon, Kruskall - Wallis, Mann-Whitney and Fisher methods.
    RESULTS:
    A significant haemoglobin drop was seen on days 9 and 14 post-vaccination. This descent was > 10 g/L in 8.2% of the cases, and > or = 6 g/L in 19.6%. Serum iron and transferrin saturation decreased significantly, whereas mean corpuscular volume, free erythrocyte protoporphyrin and serum ferritin were significantly increased. All these but protoporphyrin recovered by day 30. Subjects with normal iron metabolism figures on day 0 and those whose thermal variations were above 38 degrees C had greater changes in the figures related to iron metabolism.
    CONCLUSION:
    The evaluation of iron metabolism is not reliable if the patient has suffered from infection, although a mild viral one, in the three weeks prior to the study.

Open Questions

Haptoglobin: details
"Hemopexin.: details":
"Lactoferrin.: details":
"Transferrrin.: details":

In the "modern" oxygen-rich environment, iron is highly insoluble and has low bioavailability despite its abundance, making it the subject of fierce competition between a host and its pathogens

NRAMP, TBC, HIV

Pathways of Skeletal Muscle Atrophy: HIV as a Model System?

The Fe button below will take you to the iron cycle, allowing you to see the entire cycle as a whole.

Insulin and iron metabolism

Iron metabolism

Iron and cardiovascular disease

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Attachments
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iron-balance.gifgp07/01/2008
iron-man-1995.gifgp01/03/2009
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