MicrobiologyBytes

Iron is a highly abundant metal on earth and is vital for virtually all organisms. Despite its abundance, iron deficiency is the most prevalent nutrition disorder worldwide. It mostly affects infants, young children and women in developing countries. Iron deficiency has major health consequences such as infection, poor pregnancy outcome, and impaired physical and cognitive development. Several trials have shown that iron deficiency can be effectively controlled by both iron supplementation and fortification programmes. However, safety of iron supplementation has been questioned and there is evidence suggesting that untargeted oral iron supplementation in regions with high prevalence of malaria transmission and infectious diseases can cause an increase in infections, hospital admission and mortality in young children. This might be at least partly ascribed to iron also being an essential requirement for the growth of most bacterial species. Importantly, iron availability is frequently involved in the expression of virulence-associated properties in pathogenic bacteria:

Iron Availability Increases the Pathogenic Potential of Salmonella Typhimurium and Other Enteric Pathogens at the Intestinal Epithelial Interface. (2012) PLoS ONE 7(1): e29968. doi:10.1371/journal.pone.0029968
Recent trials have questioned the safety of untargeted oral iron supplementation in developing regions. Excess of luminal iron could select for enteric pathogens at the expense of beneficial commensals in the human gut microflora, thereby increasing the incidence of infectious diseases. The objective of the current study was to determine the effect of high iron availability on virulence traits of prevalent enteric pathogens at the host-microbe interface. A panel of enteric bacteria was cultured under iron-limiting conditions and in the presence of increasing concentrations of ferric citrate to assess the effect on bacterial growth, epithelial adhesion, invasion, translocation and epithelial damage in vitro. Translocation and epithelial integrity experiments were performed using a transwell system in which Caco-2 cells were allowed to differentiate to a tight epithelial monolayer mimicking the intestinal epithelial barrier. Growth of Salmonella typhimurium and other enteric pathogens was increased in response to iron. Adhesion of S. typhimurium to epithelial cells markedly increased when these bacteria were pre-incubated with increasing iron concentration), whereas this was not the case for the non-pathogenic Lactobacillus plantarum. Cellular invasion and epithelial translocation of S. typhimurium followed the trend of increased adhesion. Epithelial damage was increased upon incubation with S. typhimurium or Citrobacter freundii that were pre-incubated under iron-rich conditions. In conclusion, our data fit with the consensus that oral iron supplementation is not without risk as iron could, in addition to inducing pathogenic overgrowth, also increase the virulence of prevalent enteric pathogens.

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Iron is required for Staphylococcus aureus growth and persistence and hence must be acquired during infection. Most vertebrate iron is utilized as a cofactor in biochemical reactions that occur intracellularly. This intracellular pool of iron is generally not available to extracellular pathogens such as S. aureus. Moreover, the amount of free iron found within the serum is negligible, as it is usually complexed to high-affinity iron-binding proteins. This process of iron sequestration by the host, also referred to as nutritional immunity, inhibits the growth of invading microorganisms. In response to this severe iron limitation, S. aureus has evolved sophisticated strategies to obtain iron required to proliferate within vertebrates. This review provides a comprehensive analysis of the pathways S. aureus utilizes to obtain iron during infection.

Molecular Mechanisms of Staphylococcus aureus Iron Acquisition. Annual Review of Microbiology June 2, 2011 doi: 10.1146/annurev-micro-090110-102851
The unique redox potential of iron is an ideal cofactor in diverse biochemical reactions. Iron is therefore vital for the growth and proliferation of nearly all organisms, including pathogenic bacteria. Vertebrates sequester excess iron within proteins in order to alleviate toxicity and restrict the amount of free iron available for invading pathogens. Restricting the growth of infectious microorganisms by sequestering essential nutrients is referred to as nutritional immunity. In order to circumvent nutritional immunity, bacterial pathogens have evolved elegant systems that allow for the acquisition of iron during infection. The gram-positive extracellular pathogen Staphylococcus aureus is a commensal organism that can cause severe disease when it gains access to underlying tissues. Iron acquisition is required for S. aureus colonization and subsequent pathogenesis. Herein we review the strategies S. aureus employs to obtain iron through the production of siderophores and the consumption of host heme.

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Iron is a vital nutrient for virtually all forms of life. The requirement for iron is based on its role in cellular processes ranging from energy generation and DNA replication to oxygen transport and protection against oxidative stress. Bacterial pathogens are not exempt from this iron requirement, as these organisms must acquire iron within their vertebrate hosts in order to replicate and cause disease. This paper describes how they do that.

The Battle for Iron between Bacterial Pathogens and Their Vertebrate Hosts. (2010) PLoS Pathog 6(8): e1000949. doi:10.1371/journal.ppat.1000949

Related:

• How bacteria capture iron from heme
• Iron Uptake and Virulence
• Bacillus anthracis gets iron from hemoglobin
• Utilization of iron by Campylobacter jejuni

Iron is required for many cellular processes, but can be toxic at high concentrations. Thus iron homeostasis is strictly regulated so that iron acquisition, storage, and consumption are geared to iron availability, and that intracellular levels of free iron do not reach toxic levels. Recently, the roles of manganese and its control in cells have been investigated, and it is becoming clear that some aspects of the metabolism of iron and manganese are interrelated.

Control of bacterial iron homeostasis by manganese. PNAS USA May 24 2010. doi: 10.1073/pnas.100234210
Perception and response to nutritional iron availability by bacteria are essential to control cellular iron homeostasis. The Irr protein from Bradyrhizobium japonicum senses iron through the status of heme biosynthesis to globally regulate iron-dependent gene expression. Heme binds directly to Irr to trigger its degradation. Here, we show that severe manganese limitation created by growth of a Mn2+ transport mutant in manganese-limited media resulted in a cellular iron deficiency. In wild-type cells, Irr levels were attenuated under manganese limitation, resulting in reduced promoter occupancy of target genes and altered iron-dependent gene expression. Irr levels were high regardless of manganese availability in a heme-deficient mutant, indicating that manganese normally affects heme-dependent degradation of Irr. Manganese altered the secondary structure of Irr in vitro and inhibited binding of heme to the protein. We propose that manganese limitation destabilizes Irr under low-iron conditions by lowering the threshold of heme that can trigger Irr degradation. The findings implicate a mechanism for the control of iron homeostasis by manganese in a bacterium.

Related:

• Iron Uptake and Virulence
• How bacteria capture iron from heme
• Utilization of iron by Campylobacter jejuni

Heme is ubiquitous, abundant, and vitally necessary as a cofactor in oxidoreduction and gas transport. Most microorganisms display a complete heme biosynthetic pathway, but are able to acquire the essential ferrous iron from exogenous heme. Free heme or heme arising from hemoproteins is internalized intact and subsequently degraded in the cytosol. Diverse mechanisms for heme uptake have been identified in bacteria. They involve extracellular hemoproteins (hemophores) that capture heme and deliver it to bacteria and cell surface receptors that bind heme, hemoproteins, and/or hemophores. Surface receptors of Gram-positive bacteria are cell-wall anchored proteins that scavenge heme and relay it to specific ABC transporters involved in heme internalization. The absence of these newly identified mechanisms from higher eukaryotic organisms makes them potential targets for new antibacterial drugs, especially since there is growing evidence that heme utilization systems are required for bacterial virulence.

Bacteria capture iron from heme by keeping tetrapyrrol skeleton intact. PNAS USA June 29, 2009, doi: 10.1073/pnas.0903842106
Because heme is a major iron-containing molecule in vertebrates, the ability to use heme-bound iron is a determining factor in successful infection by bacterial pathogens. Until today, all known enzymes performing iron extraction from heme did so through the rupture of the tetrapyrrol skeleton. Here, we identified 2 Escherichia coli paralogs, YfeX and EfeB, without any previously known physiological functions. YfeX and EfeB promote iron extraction from heme preserving the tetrapyrrol ring intact. This novel enzymatic reaction corresponds to the deferrochelation of the heme. YfeX and EfeB are the sole proteins able to provide iron from exogenous heme sources to E. coli. YfeX is located in the cytoplasm. EfeB is periplasmic and enables iron extraction from heme in the periplasm and iron uptake in the absence of any heme permease. YfeX and EfeB are widespread and highly conserved in bacteria. We propose that their physiological function is to retrieve iron from heme.

Related:

• Iron Uptake and Virulence
• New drug targets for urinary tract bacterial infections
• Bacillus anthracis gets iron from hemoglobin
• Utilization of iron by Campylobacter jejuni
• Bacterial sensors of oxygen