Iron acquisition systems for ferric hydroxamates, haemin and haemoglobin in <i>Listeria monocytogenes</i>

Jin, Bo; Newton, S. A.; Shao, Yong; Jiang, Xiaoxu; Charbit, Alain; Klebba, Phillip E.

doi:10.1111/j.1365-2958.2005.05015.x

Cited by 74 publications

(107 citation statements)

References 82 publications

(117 reference statements)

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“…The typhoid fever agent Salmonella enterica exploits the hemophagocytic ability of BMM to survive during chronic in vivo infections (30), and heme was also shown to function as a source of iron for additional bacterial pathogens residing within macrophage phagosomes, such as Mycobacterium haemophilum and Listeria monocytogenes (31,32).…”

Section: Resultsmentioning

confidence: 99%

Heme Uptake Mediated by LHR1 Is Essential for Leishmania amazonensis Virulence

et al. 2013

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The protozoan parasite Leishmania amazonensis is a heme auxotroph and must acquire this essential factor from the environment. Previous studies showed that L. amazonensis incorporates heme through the transmembrane protein LHR1 (Leishmania Heme Response 1). LHR1-null promastigotes were not viable, suggesting that the transporter is essential for survival. Here, we compared the growth, differentiation, and infectivity for macrophages and mice of wild-type, LHR1-single-knockout (LHR1/ ⌬lhr1), and LHR1-complemented (LHR1/⌬lhr1 plus LHR1) L. amazonensis strains. LHR1/⌬lhr1 promastigotes replicated poorly in heme-deficient media and had lower intracellular heme content than wild-type parasites. LHR1/⌬lhr1 promastigotes were also less effective in reducing ferric iron to ferrous iron, a reaction mediated by the heme-containing parasite enzyme LFR1 (Leishmania Ferric Reductase 1). LHR1/⌬lhr1 parasites differentiated normally into aflagellated forms expressing amastigote-specific markers but were not able to replicate intracellularly after infecting macrophages. Importantly, the intracellular growth of LHR1/⌬lhr1 amastigotes was fully restored when macrophages were allowed to phagocytose red blood cells prior to infection. LHR1/⌬lhr1 parasites were also severely defective in the development of cutaneous lesions in mice. All phenotypes observed in LHR1/⌬lhr1 L. amazonensis were rescued by expression of episomal LHR1. Our results reveal the importance of efficient heme uptake for L. amazonensis replication and vertebrate host infectivity, reinforcing the potential usefulness of LHR1 as a target for new antileishmanial drugs.

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Section: Resultsmentioning

confidence: 99%

Heme Uptake Mediated by LHR1 Is Essential for Leishmania amazonensis Virulence

et al. 2013

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“…Molecular interactions between L. monocytogenes IsdC and hemin have not yet been reported; however, it seems likely that this polypeptide may also bind hemin. Surprisingly, mutant listeria lacking srtB, srtA, lmo2186, or svpA were not required for iron scavenging when heme or hemoglobin were the sole iron sources in disk diffusion assays on agar media (19,27). Thus, the physiological role of SvpA binding to hemin requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Surface Protein IsdC and Sortase B Are Required for Heme-Iron Scavenging ofBacillus anthracis

2006

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Bacillus anthracis, the spore-forming agent of anthrax, requires iron for growth and is capable of scavenging heme-iron during infection. We show here that the B. anthracis iron-regulated surface determinants (isd) locus encompasses isdC, specifying a heme-iron binding surface protein. Anchoring of IsdC to the cell wall envelopes of vegetative bacilli requires srtB, which encodes sortase B. Purified sortase B cleaves IsdC between the threonine and the glycine of its NPKTG motif sorting signal. B. anthracis variants lacking either isdC or srtB display defects in heme-iron scavenging, suggesting that IsdC binding to heme-iron in the cell wall envelope contributes to bacterial uptake of heme.Bacillus anthracis is a spore-forming gram-positive bacterium pathogenic to both humans and animals (20). Depending on the route of entry, disease manifests as clinically distinct syndromes-cutaneous, gastrointestinal, or inhalational anthrax, all of which are rapidly fatal unless treated early with antimicrobials (18). One hallmark of anthrax disease is rapid multiplication of vegetative bacilli to a density of 10 10 to 10 11 CFU per gram of host tissue (20). To achieve such growth, B. anthracis must satisfy its nutritional requirements for iron (4,42). Bioinformatic and genetic analyses suggest that B. anthracis can utilize diverse sources of iron that are sequestered within host iron storage and transport proteins, such as hemoglobin, lactoferrin, ferritin, and transferrin (7,21,32). The ability to acquire iron during infection is an essential attribute of many bacterial pathogens of vertebrates (3, 43). Iron is required for numerous cellular processes that are fundamental to life, such as DNA replication, energy generation, and protection against reactive oxygen species (9). Most iron in vertebrates is sequestered within cells and stored as hemoproteins in red blood cells or is bound to transferrin or lactoferrin (6). In order to scavenge iron from transferrin or lactoferrin, bacteria secrete siderophores, molecules that capture iron with high affinity for subsequent receptor-mediated uptake by bacteria (10). The most abundant group of iron binding proteins in humans are hemoproteins, polypeptides that utilize heme as a cofactor (5, 9). Heme, a tetrapyrrole encircling an individual iron atom within the macrocyclic conjunction of the heme porphyrin ring, and hemoproteins represent approximately 80% of the iron in humans (9). In order to successfully mediate infection, most bacterial pathogens have developed systems capable of extracting heme from human hemoproteins and subsequently utilizing this cofactor as both a heme and an iron source (17,34,45).The mechanism(s) whereby B. anthracis scavenges heme from host hemoproteins is not yet understood. Recent work with Staphylococcus aureus, another gram-positive pathogen, identified the isd (iron-regulated surface determinants) locus, which encodes proteins involved in heme-iron scavenging and transport (24,25). Specifically, the locus codes for proteins with binding affinity for...

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“…Haemin/ haemoglobin uptake by HupDGC and ferrichrome siderophore by Fhu systems have already been characterized (Jin et al, 2006;Xiao et al, 2011;McLaughlin et al, 2012). Although Listeria does not produce siderophores, it is able to obtain iron using either exogenous siderophores produced by other micro-organisms or natural catechol compounds widespread in the environment (Jin et al, 2006;Xiao et al, 2011). Physiological data suggest the existence of strong surface-associated ferric reductase activity in L. monocytogenes (Deneer et al, 1995;Cowart, 2002), but no genetic determinant for the enzyme has been identified in its genome.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have shown that the concentration of intracellular iron influences the transcription rates of over 200 genes in bacteria (Ochsner et al, 2002;Camejo et al, 2009;Ledala et al, 2010). Due to the low availability of iron in the host, bacteria have evolved various iron acquisition systems such as citrateinducible ferric uptake (Adams et al, 1990;Andrews et al, 2003), a cell surface transferring binding protein (Hartford et al, 1993), an ABC transporter for HN/Hb, ferric hydroxamates (fhu), haemin/haemoglobin (hup) (Brown & Holden 2002;Faraldo-Gó mez et al, 2003;Jin et al, 2006;Weinberg, 2009) and extracellular and/or surface-associated iron reductases (McLaughlin et al, 2011). Haemin/ haemoglobin uptake by HupDGC and ferrichrome siderophore by Fhu systems have already been characterized (Jin et al, 2006;Xiao et al, 2011;McLaughlin et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Due to the low availability of iron in the host, bacteria have evolved various iron acquisition systems such as citrateinducible ferric uptake (Adams et al, 1990;Andrews et al, 2003), a cell surface transferring binding protein (Hartford et al, 1993), an ABC transporter for HN/Hb, ferric hydroxamates (fhu), haemin/haemoglobin (hup) (Brown & Holden 2002;Faraldo-Gó mez et al, 2003;Jin et al, 2006;Weinberg, 2009) and extracellular and/or surface-associated iron reductases (McLaughlin et al, 2011). Haemin/ haemoglobin uptake by HupDGC and ferrichrome siderophore by Fhu systems have already been characterized (Jin et al, 2006;Xiao et al, 2011;McLaughlin et al, 2012). Although Listeria does not produce siderophores, it is able to obtain iron using either exogenous siderophores produced by other micro-organisms or natural catechol compounds widespread in the environment (Jin et al, 2006;Xiao et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Role of the twin-arginine translocase (tat) system in iron uptake in Listeria monocytogenes

et al. 2015

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The twin-arginine translocase (Tat) complex is a unique system that translocates folded proteins across the cytoplasmic membrane. In this study, the Tat transporter system in Listeria monocytogenes was characterized to determine the role of Tat in the iron uptake pathway. A putative tatAC operon, containing conserved Fur-binding sequences in the promoter region, has been predicted to encode Tat-translocase components. Another operon, fepCAB, with a putative Fur-binding sequence in the promoter, close to TatAC, was identified in the complementary strands of L. monocytogenes. Electrophoretic mobility shift assay showed that the listerial Furrepressor binds to the promoter of the tatAC operon, suggesting that tat is under Fur regulation. Using a heterologous system in a reporter assay, FepB was translocated across the membrane. Mutations in tatC and fepB were constructed to determine the roles of Tat and FepB, respectively. In a whole-cell ferric reductase assay, the fepB and tatC mutants were found to have reduced levels of ferric reductase activities compared with those of the isogenic parent strain. Although ferric reductase activity has been demonstrated in Listeria, a conventional ferric reductase encoding sequence does not appear to be present in its genome. Hence, we propose that fepB encodes a ferric reductase enzyme, which is translocated by the Tat-translocase system onto the bacterial cell surface, and plays an important role in the reductive iron uptake process in L. monocytogenes.

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Iron acquisition systems for ferric hydroxamates, haemin and haemoglobin in Listeria monocytogenes

Cited by 74 publications

References 82 publications

Heme Uptake Mediated by LHR1 Is Essential for Leishmania amazonensis Virulence

Heme Uptake Mediated by LHR1 Is Essential for Leishmania amazonensis Virulence

Surface Protein IsdC and Sortase B Are Required for Heme-Iron Scavenging ofBacillus anthracis

Role of the twin-arginine translocase (tat) system in iron uptake in Listeria monocytogenes

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