The impact of iron on Listeria monocytogenes; inside and outside the host

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As iron is vital for all cells, host sequestration of iron provides a significant barrier to bacterial infection. The absolute requirement for iron has driven the evolution of refined systems by which pathogenic bacteria such as Listeria monocytogenes can competitively acquire this element during host infection. This process is coordinated, at least partly, by the Ferric Uptake Regulator (Fur). Recent studies have identified loci within the listerial Fur-regulon and have characterized specific systems involved in iron uptake from various sources. This work has greatly advanced our knowledge of the mechanisms underpinning iron homeostasis in L. monocytogenes. A greater understanding of the molecular mechanisms by which pathogenic bacteria acquire iron is significant from both a food safety and public-health perspective.

Introduction

L. monocytogenes is a Gram-positive, intracellular pathogen responsible for the potentially fatal disease listeriosis. L. monocytogenes is justifiably recognized as a significant public-health problem, with clinical manifestations including febrile gastroenteritis in healthy individuals [1], sepsis in the immuno-compromised, and miscarriage in pregnant women. The ability of this bacterium to acquire and utilize iron is not only essential during infection but could also support its growth and survival in many diverse environmental niches.

Iron is an indispensable element for nearly all living cells, primarily owing to its involvement in respiratory pathways and its role as a cofactor for numerous cellular enzymes. Competition for this ‘precious’ resource, particularly during systemic infection, can help to determine the outcome for both host and pathogen. Often referred to as ‘nutritional immunity’ [2], the host has developed sophisticated mechanisms to limit infection through iron sequestration. In turn, this has forced invading bacteria such as L. monocytogenes to develop counter-strategies to overcome these iron-dependent host immune responses. We will review recent findings involving the sequestration and acquisition of iron by both host and pathogenic cells. More specifically, we will focus on current investigations of iron homeostasis in Listeria, the importance of iron during listerial infection and the host immune response to this model intracellular pathogen. In addition, we briefly describe how the food industry is exploiting this necessity for iron to prevent bacterial contamination and how the immunogenic properties of iron transport proteins provide the potential for the development of vaccines.

Section snippets

Fur and bacterial iron homeostasis

Iron homeostasis in most bacteria, including Listeria, is controlled by the regulatory protein Fur (ferric uptake regulator) or a functional equivalent [3]. In the presence of sufficient levels of iron, Fur acts as a repressor in that a Fur–iron complex prevents gene transcription by binding to a specific Fur-box sequence [4]. Recent characterization of the Fur protein in L. monocytogenes has described the interaction between Fur and its promoter and proposes that in vitro binding does not

Iron acquisition during infection

The relationship between iron and bacterial infection has been well documented over the past 30 years. More specifically, the direct correlation between iron availability inside the host and the ability of L. monocytogenes to cause infection is corroborated by a patient undergoing long-term hemodialysis. Canavese et al. [16] have reported that iron overload is a familiar side effect in patients undergoing this treatment. Consequently, iron-rich blood specimens of a hemodialysis patient were

Restricting iron availability in food

The food industry is exploiting iron-binding proteins such as lactoferrin and ovotransferrin as agents to reduce bacterial contamination of food. The antibacterial impact of lactoferrin stems partly from its ability to sequester iron with an extremely high affinity, even more so than transferrin. It has also been reported that lactoferrin causes disruption of bacterial membranes, blocks bacterial adhesion to both abiotic and cell surfaces, and decreases bacterial invasion of mammalian cells [39

Fri, iron storage, and vaccine development

The storage of iron is also seen to influence the host–pathogen relationship. Similar to the host, bacteria use ferritin-like proteins for the storage of this metal, but recent findings show the host can target these storage proteins as part of the humoral immune response. The L. monocytogenes genome was shown to possess one ferritin encoding gene, designated fri, which recently was identified as a member of the Fur-regulon and is considered necessary for full listerial infection [8••, 46, 47].

Conclusions

A greater understanding of the molecular mechanisms by which pathogenic bacteria maintain iron homeostasis could make a significant contribution to both food safety and human health. It is evident that the pathogenesis of L. monocytogenes depends on the employment of a variety of mechanisms that facilitate iron acquisition during host infection. Recent progress in the identification of specific iron transport and storage proteins in L. monocytogenes could offer significant therapeutic

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Heather McLaughlin was supported by a post-graduate studentship from the Irish Research Council for Science, Engineering and Technology (IRCSET), 2006–2009. All authors acknowledge the support of the Alimentary Pharmabiotic Centre funded by the Science Foundation of Ireland Centres for Science Engineering and Technology (CSET) programme.

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