Mol Microbiol. 2014 Jan;91(1):98-109.

IdeR is required for iron homeostasis and virulence in Mycobacterium tuberculosis.

Pandey R, Rodriguez GM.

Public Health Research Institute at New Jersey Medical School, Rutgers State University of New Jersey, 225 Warren Street, Newark, NJ, 07103, USA.

 

ABSTRACT:

Iron is an essential but potentially harmful nutrient, poorly soluble in aerobic conditions, and not- freely available in the human host. To acquire iron, bacteria have evolved high affinity iron acquisition systems that are expressed under iron limitation often in conjunction with virulence determinants. Because excess iron can be dangerous, intracellular iron must be tightly controlled. In mycobacteria, IdeR functions as a global iron dependent transcriptional regulator, but because inactivation of ideR is lethal for Mycobacterium tuberculosis, it has not been possible to use genetics to fully characterize this protein’s function or examine the requirement of iron regulation during tuberculosis infection. In this work, a conditional M. tuberculosis ideR mutant was generated and used to study the basis of IdeR’s essentiality. This investigation uncovered positive regulation of iron storage as a critical aspect of IdeR’s function in regular culture and a prominent factor for survival under stresses associated with life in macrophages. Moreover, this study demonstrates that IdeR is indispensable in the mouse model of tuberculosis, thereby linking iron homeostasis to virulence in M. tuberculosis

PMID: 24205844

 

SUPPLEMENT:

Iron is an essential nutrient for most living organisms. It is necessary for the activity of enzymes that mediate vital cellular functions ranging from respiration and basic metabolism to DNA replication. Although iron is very abundant in nature, it is insoluble in the presence of oxygen and at neutral pH. For this reason it is always bound to proteins that keep it in solution, and not freely available to pathogens that infect a human host. For this reason, to establish a successful infection, pathogens must be able to compete for iron. Mycobacterium tuberculosis, the bacterium that causes human tuberculosis has solved the problem of iron acquisition by producing and secreting siderophores. Siderophores are potent iron chelators that can solubilize free iron or remove it from iron-binding protein complexes and deliver it to the bacterial cell via specialized iron-siderophore transporters.

Although essential, iron can also be harmful, because it catalyzes oxygen based free radical formation (Figure 1). Oxygen radicals are highly toxic to cells. They can damage DNA, proteins, lipids and polysacharides. Consequently, iron dependent aerobic organisms must carefully control intracellular iron. This control is implemented at the level of gene transcription. Genes encoding proteins necessary for siderophore synthesis and iron acquisition are actively transcribed when the cell experiences iron limitation and repressed when the cell has achieved iron sufficiency. During iron sufficiency, the transcription of genes encoding iron storage proteins is elevated, so that iron is kept in a safe way.

Our laboratory studies how M. tuberculosis adapts to changes in iron availability in the different environments in which it survives and replicates during infection. In previous work, we identified the transcriptional regulator that controls the expression of iron uptake and storage genes in M. tuberculosis. This regulator is named IdeR. The paper featured in this site, examined the relevance of IdeR for iron homeostasis and virulence of this pathogen. Because deleting the ideR gene in M. tuberculosis is lethal under the standard culture conditions in the laboratory, we generated a conditional mutant strain. In this mutant, we basically placed a “switch” in front of the ideR gene that allow us to turn off the synthesis of IdeR and examine how the lack of this protein affected M. tuberculosis in its ability to control iron homeostasis and to multiply in a mouse model of tuberculosis.

Our findings (summarized in figure 2) demonstrate that: 1. By repressing iron uptake and increasing iron storage IdeR is indispensable for M. tuberculosis to maintain iron homeostasis, preventing iron overload and its toxic effects. 2. M. tuberculosis lacking IdeR becomes prone to iron mediate toxicity and vulnerable to the antimicrobial effects of macrophages. 3. Lack of IdeR precludes the ability of M. tuberculosis to proliferate and cause disease in infected mice.

Tuberculosis (TB) is the cause of death of more than one million people each year and the continued rise of multidrug resistant strains threatens TB control efforts. The significance of our results lies in the identification of iron homeostasis as an essential process for M. tuberculosis survival in the host and IdeR as a novel potential target for development of new therapeutics against TB.

figure-121Figure 1. Fenton reaction. In the presence of hydrogen peroxide ferrous iron catalyzes the Fenton reaction generating toxic oxygen radicals.

 

figure2Figure 2. IdeR is the master regulator of iron homeostasis in Mtb. A. IdeR binds iron and as a dimer complex binds to DNA and represses the transcription of genes involved in iron acquisition (siderophore synthesis, export and import) while up-regulating iron storage to prevent iron mediated toxicity. B. In the absence of IdeR Mtb is unable to control iron uptake, excess iron is not properly stored and it fuels reactive oxygen species generation which cause oxidative damage of proteins, lipids and DNA.

 

Acknowledgment:

The work presented in the featured paper was supported by NIH grant AI044856.

Contact Information:

G. Marcela Rodriguez: rodrigg2@njms.rutgers.edu

http://www.phri.org/research/res_pirodriguez.asp

Public Health Research Institute at New Jersey Medical School, Rutgers State University of New Jersey, 225 Warren Street, Newark, New Jersey 07103.

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