Indian Journal of Medical Microbiology
Medknow Publications on behalf of Indian Association of Medical
Microbiology
ISSN: 0255-0857
Vol. 24, Num. 3, 2006, pp. 163-164
Indian Journal of Medical Microbiology, Vol. 24, No. 3, July-
September, 2006, pp. 163-164
Guest Editorial
Iron and bacterial virulence
Sritharan M
School of Life Sciences, University of Hyderabad, Hyderabad - 500 046,
AP
Correspondence Address:School of Life Sciences, University of
Hyderabad, Hyderabad - 500 046, AP,
srimanju@yahoo.com
Code Number: mb06051
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.[1] There is direct evidence to show that iron, in
association with the iron-regulator Fur (in many gram negative
organisms)/DtxR (in several gram positive organisms) operates at the
molecular level and acts as a regulatory molecule, controlling not
only the iron acquisition machinery but the expression of toxins and
other bacterial virulence determinants, that are not related to iron
metabolism.[2]
So, how do iron levels play an important role in infection? Low iron
levels have been shown to induce the expression of a number of
bacterial toxins and virulence factors. 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. This was perhaps nature′s
way of restricting the level of this element, whose toxicity is well
known due to its role in the generation of free radicals. The
mammalian host maintains low levels of circulating free iron by means
of its iron-binding proteins, the extracellular transferrin and
lactoferrin and the intracellular ferritin, haemosiderin and haeme.
Normal human transferrin is about 30% saturated with iron and has a
high association constant for Fe 3+ which ensures that the amount of
free Fe 3+ in plasma is about 10 -18 M. Lactoferrin, predominantly
found in polymorphonuclear leukocytes and macrophages, the first lines
of defense against an invading pathogen, has a greater affinity for
iron and 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
and bacteriostatic effect of plasma, lymph or cell-free exudates.
Kochan[3] 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.
The question now arises as to how pathogens multiply successfully in
vivo despite this severe restriction of freely available iron? To
obtain host iron, successful pathogens employ one of the following
strategies: (1) production of low molecular weight Fe 3+ specific
ligands called siderophores that chelates iron from host iron-binding
proteins, followed by uptake of the ferric siderophore via specific
cell surface receptors, the iron-regulated membrane/envelope proteins
(IRMPs/IREPs), (2) direct uptake of iron from host iron-containing
molecules via specific receptors that include receptors for hemin,
hemoglobin, transferrin, lactoferrin. Escherichia coli provided an
ideal experimental model for the understanding of adaptation of
bacteria to iron-restriction and today there is a vast amount of
information from E. coli about iron acquisition systems and molecular
mechanisms of iron acquisition machinery.[4] About 6 iron acquisition
systems have been identified in E. coli and one among them is the
enterobactin-mediated high affinity transport system seen not only in
E. coli but also in Klebsiella pneumoniae , Salmonella typhimurium and
some species of Shigella . The secreted siderophore enterobactin (also
called enterochelin) is taken up by a TonB-dependant outer membrane
receptor, the ferric-enterobactin receptor FepA. A wide range of
bacterial siderophores and their receptors have been extensively
reviewed.[5],[6] The second important mechanism of iron acquisition is
seen in a number of human and animal pathogens and in particular the
members of the Pasteurellaceae and Neisseriaceae[7] that exploit a
siderophore-independent mechanism for acquiring iron from host iron-
binding proteins. These pathogens express specific cell surface
receptors and there is direct contact between these receptors and the
host iron-binding proteins followed by removal of the iron directly
from the latter. These receptors are highly specific as exemplified by
the high degree of specificity of human transferrin as compared to
that from other species. Bacterial receptors for transferrin,
lactoferrin, haemin, haemoglobin are well understood, both in
chemistry and in uptake mechanisms. All the iron-controlled genes,
irrespective of the nature of the iron-acquisition system, are
regulated by level of intracellular iron in association with the iron
regulator Fur/DtxR, the details of which are well deciphered in E.
coli . The Fur protein is a repressor molecule, which on complexing
with Fe 2+ blocks the transcription of iron-regulated genes by binding
to specific operator sequences called Fur box/ Iron box within their
promoter regions, whose consensus sequence was determined as 5′-
GATAATGATAATCATTATC.
Overwhelming evidence has accumulated over the past decade[2] that
shows that iron-restricted conditions favoured the expression of a
number of toxins and other potential virulence determinants: few
examples include diphtheria toxin by Corynebacterium diphtheriae , a-
hemolysin by E. coli , Shiga toxin by Shigella dysenteriae ,
verocytotoxin by E. coli and exotoxin A by Pseudomonas aeruginosa .
The association of iron and virulence is obvious. 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 and iron, along with other cellular nutrients for utilization by
the infecting bacteria. Molecular mechanisms of regulation of the
expression of tox gene in C. diphtheriae showed that in the presence
of sufficient intracellular iron, the DtxR-Fe 2+sub complex bound to
the iron box upstream of the tox gene and inhibited its transcription,
while upon iron deprivation, there was induction of its expression as
the DtxR cannot bind to the iron box in the absence of Fe 2+ .
The importance of iron in tuberculosis has been well described by
Ratledge,[8] with emphasis on understanding the basic mechanisms of
the pathogenesis of this disease, that has assumed to be one of the
worst bacterial disease in terms of the number of deaths per year.
This is particularly important in our country, with reports of
tuberculosis being the leading killer among the infectious diseases.
It has been aptly brought out by the author 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 is detrimental as the
increased availability of iron increases multiplication of bacterial
growth, again contributing to increased virulence, as demonstrated
experimentally. While iron is important in the establishment of an
infection, it appears that iron may also play a role in the effect of
anti-bacterial agents. Our observations on the effect of iron
deprivation on the anti-tubercular drug INH on Mycobacterium
tuberculosis grown in vitro showed that the peroxidase activity of the
catalase-peroxidase KatG is abolished upon iron limitation, resulting
in the failure of activation of the prodrug INH to active form.[9] The
potentiating effect of iron on another anti-mycobacterial drug
pyrazinamide was also shown by Somoskovi et al .[10]
While it is clear that iron levels are important in infection, it is
not an easy task to control their levels in the host. The pros and
cons of low and high iron levels, as explained above needs to be
considered by the physician in treating a patient with chronic
infection. In tuberculosis, for example, 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 ad 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. There should a slow influx of iron with monitoring
of the levels at regular intervals to effectively control the
infection.
References
1. Salyers AA, Whitt DD. Virulence factors that damage the host. In:
Bacterial Pathogenesis. A Molecular Approach. New York: ASM Press;
1994. p. 47-62. Back to cited text no. 1
2. Griffiths E, Chart H. Iron as a regulatory signal in Iron and
Infection 2nd ed. Edited by JJ Bullen and Griffiths E. 1999. p.
213-54. Back to cited text no. 2
3. Kochan I. Role of iron in the regulation of nutritional immunity.
Bioorganic Chem 1976; 2 :55-7. Back to cited text no. 3
4. Braun V, Hantke K, Koster W. Bacterial iron transport: mechanisms,
genetics and regulation. In : Metal Ions in Biological systems. Sigel
A, Sigel H, editors. Iron transport and storage in Microorganisms,
Plants and Animals. New York: Marcel Dekker; 1998. p. 67-145. Back
to cited text no. 4
5. Ratledge C, Dover LG. Iron metabolism in pathogenic bacteria . Annu
Rev Microbiol 2000; 54: 881-941. Back to cited text no. 5 [PUBMED]
[FULLTEXT]
6. Sritharan M. Iron as a candidate in virulence and pathogenesis in
mycobacteria and other microorganisms. World J Microbiol Biotechnol
2000; 16 :769-80. Back to cited text no. 6
7. Genco CA, Desai PJ. Iron acquisition in the pathogenic Neisseria.
Trends Microbiol 1996; 4 :179. Back to cited text no. 7 [PUBMED]
[FULLTEXT]
8. Ratledge C. Iron mycobacteria and tuberculosis. Tuberculosis 2004;
84 :110-30. Back to cited text no. 8 [PUBMED] [FULLTEXT]
9. Sritharan M, Yeruva VC, Sundaram Sivagami CA, Duggirala S. Iron
enhances the susceptibility of pathogenic mycobacteria to isoniazid,
an anti-tubercular drug Available Online in World J Microbiol
Biotechnol May 2006. Back to cited text no. 9
10. Somoskovi A, Wade MM, Sun Z, Zhang Y. Iron enhances the
antituberculous activity of pyrazinamide. J Antimicrob Chemother 2004;
53: 192-6. Back to cited text no. 10 [PUBMED] [FULLTEXT]
Copyright 2006 - Indian Journal of Medical Microbiology
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