Title: Iron & Bacterial Virulence
Authors
: Sritharan M
Journal
: Indian J Med Microbiol 2006;24:163-164
Type of Article
: Review article
Presented By
Dr. Umme Habiba
Introduction
• An invading pathogen must have the ability to
multiply successfully within the hostile environment
of the mammalian host to establish an infection
• Bacterial and other pathogens produce a range of
virulence determinants required for pathogenicity,
many of which are regulated by environmental
factors; level of iron is one of the important factors
intimately connected to the synthesis of some of the
virulence determinants
• A regulatory molecule controlling not only the iron
acquisition machinery but the expression of toxins
and other bacterial virulence determinants
 Do pathogenic bacteria encounter conditions of iron
limitation within the mammalian host?
• Iron is an essential nutrient, Which by virtue of its low
solubility at biological pH is not easily available.
• The mammalian host maintains low levels of circulating
free iron by means of its iron binding proteins.
which are
a. Extra cellular : i. Transferrin,
ii. Lactoferrin
b. Intercellular:i. Ferritin, ii. Haemosiderin,iii. Haeme
• Lactroferrin, Predominantly found in polymorphonucler
leukocytes & macrophages the first lines of defense
against an invading pathogen, has a greater affinity for
iron & possesses the additional property of holding the iron
at the low pH prevailing in the immediate environment of
the inflammatory sites.
• These two molecules account significantly for the
bactericidal & bacteriostatic effect of plasma, lymph
or cell-free exudates
• KOCHAN referred this phenomenon of limiting
the iron availability to an invading pathogen as
“nutritional immunity”. There is no involvement of
the immune system in this process.
• Circulating iron levels are lowered by increased
synthesis
of
transferrin
and
ferritin
with
simultaneous suppression of the assimilation of
dietary iron by decreasing its absorption by the
intestine.
 How pathogens multiply successfully in vivo despite this
severe restriction of freely available iron ?
i. Production of low molecular weight Fe3+ specific
ligands called siderophores that chelates iron from
host iron-binding proteins, followed by uptake of the
ferric siderophores via specific cell surface receptros,
the iron regulated membrane/envelope proteins
(IRMPs/IREPs ). Escherichia coli, salmonella
typhimurium, klebsiella pneumoniae, some
species of shigella acts by this mechanism.
ii. Direct uptake of iron from host iron-containing
molecules via specific receptors that include
receptors for hemin, hemoglobin, transferrin,
lactoferrin. Pasteurellaceae & Neisseriaceae acts
by this mechanism.
Iron restricted conditions
Overwhelming evidence has accumulated over the
past decade that shows that iron-restricted
conditions favoured the expression of a number of
toxins and other potential virulence determinants:for
examples
▪ Diphtheria toxin by corynebacterium diphtheriae
▪ Hemolysin by E.coli
▪ Shiga toxin by shigella dysenteriae
▪ Verocytotoxin by E.coli
▪ Exotoxin by pseudomonas aeruginosa
It is clear that pathogens employ these molecules for
gaining access to host nutrients, by effecting host
cell lysis. Haemolysins, for example cause the lysis
of not only erythrocytes but all cells resulting in the
release of haeme & iron, along with other cellular
nutrients for utilization by the infecting bactria.
 Importance of iron in tuberculosis
▪ It has been well described by Ratledge, that
iron level is very crucial in the outcome of an
infection. While the host tries to limit infection by
lowering iron, there is adaptation by the pathogen
with increased expression of virulence factors, causing
damage to the host.
▪ At the same time, administration of iron
increases multiplication of bacterial growth, again
increases virulence, as demonstrated experimentally
▪ Our observations on the effect of iron
deprivation on the antitubercular drug INH on
M.Tuberculosis grown in vitro showed that the
peroxidase activity of the catalase-peroxidase Kat G is
abolished upon iron limitation, resulting in the failure
of activation of the prodrug INH to active form.The
potentiating effect of iron on pyrazimamidewas also
Conclusion
While it is clear that iron levels are important in
infections, it is not an easy task to control their levels in
the host. The pros & cons of low & high iron levels, as
explain above needs to be considered by the physician in
treating a patient with chronic infection.
For example, in tuberculosis, administering iron to
a patient presenting with anemia with a low blood cell
count needs to be done with caution.
The iron-withholding capacity of the host serves to
control the infection & if this is compromised by iron
supplements, this favors the pathogen rather than
benefiting the host. This, of course needs to be weighed
against the consequences of severe anemia, if left
untreated.
So, there should be a slow influx of iron with
monitoring of the levels at regular intervals to effectively
control the infection.