Oral Microbiology Unit, Department of Oral and Dental Science, University of Bristol, Dental School and Hospital, Lower Maudlin Street, Bristol BS1 2LY, UK1
Author for correspondence: Howard F. Jenkinson. Tel: +44 117 928 4358. Fax: +44 117 928 4313. e-mail: howard.jenkinson{at}bristol.ac.uk
Keywords: Bacillus development, virulence, oxidative stress, Streptococcus, metal ion transport
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Overview |
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In prokaryotic cells, which lack internal compartmentalization, metal ion homeostasis is maintained primarily by tight regulation of metal cation flux across the cytoplasmic membrane. Studies on transition metal ion homeostasis in bacteria have focused mainly on Fe metabolism (reviewed by Braun & Killmann, 1999 ). The acquisition of Fe poses unique problems because of the poor solubility of Fe(III) species that predominate around neutral pH in oxygenated environments. Furthermore, Fe is tightly sequestered by eukaryotic proteins, so the ability of bacteria to wrest Fe from the host is fundamental to the pathogenesis of many infectious diseases. Despite these potential difficulties, many bacteria accumulate relatively high levels of Fe. For example, laboratory-cultured Escherichia coli cells contain greater than fivefold more Fe than Mn (Posey & Gherardini, 2000
). Fe is required as an essential cofactor for many proteins, including components of the respiratory chain (cytochromes, cytochrome oxidase), tricarboxylic acid cycle (aconitase, succinate dehydrogenase) and oxidative defence systems [catalase, peroxidase, superoxide dismutase (SOD)]. Microbial Fe acquisition has been extensively studied and shown to occur by at least three very different strategies. These include the production of small molecules (siderophores) to chelate extracellular Fe3+, the direct capture of Fe3+ from host Fe-containing proteins such as transferrin, lactoferrin or haem proteins, and the uptake of Fe2+ by the Feo transport system (Braun & Killmann, 1999
). Within cells, unbound Fe2+ (and Cu+) ions are especially noxious because they catalyse Fenton-type reactions that lead to the production of damaging hydroxyl radicals (Pierre & Fontecave, 1999
). By contrast, Mn(II) is highly soluble and does not catalyse hydroxyl radical formation (Cheton & Archibald, 1988
).
Interestingly, new experimental and genomic sequence data suggest that some micro-organisms may have no requirement for Fe, having evolved metabolic and survival strategies that can be accommodated by Mn. For example, the Lyme disease pathogen Borrelia burgdorferi appears to have an obligate requirement for Mn (Posey & Gherardini, 2000 ). In the absence of Fe, the cell is limited in reactions that can be carried out; for example, aerobic respiration is impossible without cytochromes. However, the ability to forgo Fe may confer a selective advantage in natural environments in which there is intense competition for available Fe. An absolute requirement for Mn, whether in place of or in addition to Fe, would necessitate acquisition of strategies to effectively compete for Mn. Indeed, high-affinity uptake of Mn2+ was reported in E. coli over three decades ago (Silver & Lusk, 1987
), but the candidate gene for a high-affinity transporter was identified only last year (Kehres et al., 2000
). Also, bacterial transcriptional regulators that respond to Mn2+ have only recently been discovered, with homologous protein families shown to be present across the eubacteria (Posey et al., 1999
; Jakubovics et al., 2000
; Que & Helmann, 2000
). This review will summarize some of the intracellular functions of Mn and discuss recent advances that have been made in understanding the mechanisms utilized by bacteria for Mn uptake and homeostasis.
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Cellular functions of Mn |
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Bacillus development
Early work in the 1950s demonstrated that Mn is unique amongst the transition metals in promoting both endospore formation and spore germination in Bacillus (Charney et al., 1951 ; Gould, 1969
). Recent genetic studies have shown that Mn homeostasis is essential for efficient sporulation in Bacillus subtilis (Que & Helmann, 2000
), and that Mn appears to be important at several stages in the developmental cycle (Fig. 1
). Sporulation in B. subtilis involves a complex sequence of transcriptional changes, controlled by several different
factors, which are themselves subject to spatial and temporal regulation (Kroos et al., 1999
). The initial decision to sporulate is triggered by starvation, and is transcriptionally evoked by
A. At this time, cells are exquisitely sensitive to ROS, so that exposure of bacteria to paraquat, which generates intracellular superoxide (
), at a concentration that does not affect vegetative growth, results in sporulation arrest (Inaoka et al., 1999
). MnSOD has been shown to play a crucial protective role since inactivation of the sodA gene markedly reduces the paraquat concentration required to inhibit sporulation, while provision of sodA on a multicopy plasmid results in increased sporulation efficiency in the presence of paraquat (Inaoka et al., 1999
). In the switch from symmetric to asymmetric cell division, which signals commitment to sporulation, Mn2+ is directly involved as a cofactor of the SpoIIE serine phosphatase (Schroeter et al., 1999
). This is a bifunctional protein that influences polar septum formation through interactions with FtsZ (King et al., 1999
), and that separately activates
F in the forespore by dephosphorylation of SpoIIAA (Kroos et al., 1999
). It is not yet clear how SpoIIE activates
F in the forespore, but not in the mother cell, since SpoIIE and
F are present in both cell types (King et al., 1999
). It has been suggested that an inhibitor may bind to SpoIIE in the forespore, thus delaying activation until the septum is complete (Arigoni et al., 1999
). However, since Mn2+ accumulates specifically within the developing forespore, it is possible that
F activation by SpoIIE may be Mn2+-regulated.
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Oxidative stress
One of the major challenges facing bacteria growing in oxygenated environments is to efficiently resist or repair damage caused by ROS such as , H2O2 and hydroxyl radicals (·OH). Oxidative stress may be induced endogenously, for example by the oxidation of flavoproteins during respiration, or exogenously, by phagocytic production of ROS (Miller & Britigan, 1997
). Therefore, enzymes for protection against reactive oxygen, including SODs, catalases and peroxidases, are ubiquitous in bacteria. Fe is inextricably linked to oxidative damage, primarily through the ability of Fe2+ to reduce H2O2 (Touati, 2000
). One strategy for minimizing oxidative damage therefore involves limiting intracellular Fe content. In fact, there is good evidence that Lactobacillus plantarum and B. burgdorferi have dispensed with Fe requirements (Archibald, 1986
; Posey & Gherardini, 2000
), and also that several species of streptococci can grow in the absence of Fe (Spatafora & Moore, 1998
; Niven et al., 1999
; Jakubovics et al., 2000
). Where bacteria grow in the absence of Fe they appear to have an absolute requirement for Mn2+.
Bacteria have acquired elaborate defence mechanisms that co-ordinate Fe-sensing and Mn-sensing with oxidative stress responses (Bsat et al., 1998 ; Storz & Imlay, 1999
). While Fe2+ is toxic and can promote ·OH radical formation, Mn2+-containing compounds react with
, H2O2 and ·OH, without generating deleterious free radical species (Cheton & Archibald, 1988
; Stadtman et al., 1990
). Mn is essential for the detoxification of ROS in most bacteria, principally as a cofactor for MnSOD (SodA). However, several groups of lactic acid bacteria incorporate high levels of intracellular Mn2+ as a protectant in place of enzymic SOD (Archibald, 1986
). Simple Mn(II) salts can also substitute for SOD activity in SOD-deficient laboratory mutants, providing increased resistance to toxic effects of
anions (Inaoka et al., 1999
). The precise mechanism by which non-enzymic Mn2+ scavenges
in bacteria is not understood, but requires considerably higher intracellular Mn2+ levels than those needed for efficient MnSOD-mediated protection. In natural environments, enzymic SOD is probably dispensable only in bacteria such as L. plantarum that grow on Mn2+-rich plant material.
Resistance to the toxic effects of superoxide anions more usually involves the concerted activities of two or more SOD enzymes. E. coli possesses three SOD activities: periplasmic Cu/ZnSOD (SodC) and two cytosolic proteins, FeSOD (SodB) and MnSOD (SodA) (Fridovich, 1995 ). The precise function of Cu/ZnSOD is unclear at present, but it has been suggested that this protein may protect against exogenous
. Disruption of the sodA and sodB genes in E. coli leads to enhanced sensitivity of cells to
and generates nutritional auxotrophies resulting from inactivation of dihydroxy-acid dehydratase by
(Kuo et al., 1987
). On the other hand, it appears that B. subtilis (Inaoka et al., 1999
) and most streptococci and enterococci (e.g. Niven et al., 1999
), may produce only MnSOD. Inactivation of the sodA gene in Streptococcus pyogenes sensitizes these cells to
(Gibson & Caparon, 1996
), and in Streptococcus pneumoniae reduces virulence in intranasal infection of mice (Yesilkaya et al., 2000
). The cytoplasmic MnSOD in Strep. pyogenes is also secreted to the cell surface (Gerlach et al., 1998
), where it may interact with exogenous
. One of the most likely explanations for reduced virulence of bacteria that have defects in Mn2+ uptake is that they are impaired in ability to cope with oxidative stress. Another important function of enzymic Mn is in the detoxification of H2O2 by mangani-catalase. Mangani-catalases have been described in L. plantarum and Thermus thermophilus (Whittaker et al., 1999
), and recently in a range of Gram-negative bacteria (Robbe-Saule et al., 2001
).
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Mn2+ transport systems |
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ABC transporters
The mntCAB operon of Synechocystis encodes a solute-binding extracytoplasmic protein (MntC), a cytoplasmic ATP-binding component (MntA) and a transmembrane protein (MntB). Protein MntC shares 32% amino acid sequence identity with ScaA in Streptococcus gordonii, previously identified as a lipoprotein associated with an ABC transporter of unknown function (Kolenbrander et al., 1994 ). ScaA-like proteins have been found across the streptococci and enterococci (Burnette-Curley et al., 1995
; Berry & Paton, 1996
; Singh et al., 1998
; Kitten et al., 2000
). They constitute a family of proteins originally designated LraI (Jenkinson, 1994
) and now recognized as a new cluster of solute-binding proteins for metal ion transport (Dintilhac et al., 1997
). In Strep. gordonii (Kolenbrander et al., 1998
) and Strep. pneumoniae (Dintilhac et al., 1997
), the scaCBA and psaBCA operons encode the components of ABC-type uptake systems for Mn2+. The Km of the Strep. gordonii Sca transporter was estimated at 0·10·3 µM (Kolenbrander et al., 1998
), somewhat lower than that of the Mnt permease in Synechocystis sp. PCC 6803 (Bartsevich & Pakrasi, 1995
). In addition to the Psa (Mn2+) transporter, Strep. pneumoniae expresses an ABC-type Zn2+ permease, encoded by the adcCBA genes, and this is thought to transport Mn2+ also (Dintilhac et al., 1997
). Mutations in the Strep. gordonii sca genes, or in the Strep. pneumoniae psa genes, affect Mn2+ uptake and reduce the abilities of cells to undergo DNA-mediated transformation (Dintilhac et al., 1997
; Kolenbrander et al., 1998
).
The form of Mn2+ that is transported by the ABC-type permeases has not been determined. Future studies will be facilitated by assays of substrate binding by purified solute-binding proteins or reconstituted transport systems. The cation specificity of the Strep. pyogenes LraI lipoprotein MtsA was investigated by ligand blotting (Janulczyk et al., 1999 ) and shown to be relatively broad, with specificity for Zn2+, Fe3+ or Cu2+, but surprisingly not for Mn2+. The X-ray crystal structure of pneumococcal PsaA has been determined to 2·0
resolution and Zn2+, rather than Mn2+, was bound to the recombinant protein (Lawrence et al., 1998
). Thus, evidence for direct binding of Mn2+ ions to the solute-binding components of ABC transporters is not convincing. The possibility that Mn2+ is bound and transported as a chelated complex cannot be ruled out. Uptake of Mn2+ by the P-type ATPase of L. plantarum is stimulated by citrate and other tricarboxylic acids, although citrate does not seem to be imported (Archibald, 1986
; Hao et al., 1999
).
Nramps
Mn2+ uptake in bacteria can be inhibited by uncouplers (Silver & Lusk, 1987 ), and the discovery in bacteria of proteins belonging to the Nramp transporter family (Kehres et al., 2000
; Que & Helmann, 2000
), accounts for this observation. The Nramp proteins form a class of pH-dependent divalent transition metal cation transporters that are required for intestinal Fe uptake and for host macrophage cell resistance to chronic bacterial infections (Gruenheid & Gros, 2000
). The substrate specificity and cation uptake kinetics of the E. coli Nramp homologue MntH (Kehres et al., 2000
) suggest that this transporter corresponds to the Mn2+ uptake system originally described over 30 years ago. Several other bacterial Nramps have been characterized to date, and inspection of genomic sequence data shows that they are widespread throughout many diverse groups of eubacteria. A primary role for the Nramp-like proteins in E. coli and Salmonella typhimurium may be to help protect cells against ROS, a function that is particularly important during infection of the host (Kehres et al., 2000
; see below).
Cation export
Transition metal cations, including Co2+, Ni2+, Cu2+ and Zn2+, are actively extruded from bacterial cells (Silver, 1996 ) and regulation of export systems contributes significantly to the homeostatic control of these metal ions. In many cases, genes encoding metalloregulatory proteins are adjacent to those encoding the export apparatus. In Synechocystis sp. PCC 6803, an operon containing nine ORFs encodes the components required for the independent sensing and export of Ni2+, Co2+ and Zn2+ (García-Domínguez et al., 2000
). It is possible that regulated export systems for Mn2+ exist, but no system for export of Mn2+ by bacteria has yet been demonstrated.
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Transcriptional regulation |
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Mn2+-sensing occurs widely in bacteria and influences both Mn2+ homeostasis and genes involved in the oxidative stress response. Several regulatory proteins related to C. diphtheriae DtxR have recently been shown to respond uniquely to Mn2+ (Posey et al., 1999 ; Jakubovics et al., 2000
; Que & Helmann, 2000
). These proteins provide a common mechanism for the control of Mn2+ permease production. When intracellular levels of Mn2+ rise, the metallorepressor (designated ScaR in Strep. gordonii) binds with high affinity to the transporter operon promoter, thus inhibiting transcription. Under limiting Mn2+, the apoprotein dissociates from the promoter control region such that repression is rapidly relieved, with upregulation of transcription and corresponding increase in permease levels (Jakubovics et al., 2000
). In B. subtilis, the metallorepressor MntR is a bifunctional protein. It activates transcription of mntABCD encoding the ABC transporter in low Mn2+, but represses expression of the Nramp transporter encoded by mntH in Mn2+-replete conditions (Que & Helmann, 2000
). Disruption of the negative regulatory control mechanisms on Mn2+ uptake may sensitize cells to Mn2+ toxicity. For example, overexpression of mntH encoding the Nramp transporter on a high-copy-number plasmid in E. coli or Sal. typhimurium decreases the growth rates of cultures in media containing >10 µM Mn2+ (Kehres et al., 2000
). Likewise, constitutive derepression of mntH expression in B. subtilis, as a result of inactivating the metalloregulator gene mntR, greatly sensitizes the cells to Mn2+ (Que & Helmann, 2000
). Interestingly, a mntA knockout mutant in the ABC transporter was also more sensitive to Mn2+, presumably because the MntH channel was upregulated in this strain (Que & Helmann, 2000
). Thus, the co-ordinated expression and activities of the transporters are necessary for the cells to be able to respond to fluctuations in external Mn2+.
It is not yet known whether the Mn2+-specific DtxR-like proteins have global effects on transcription. Oxidative stress response genes are controlled in response to Mn2+ by the PerR metallorepressor, which shares about 28% identity with Fur protein. B. subtilis PerR responds to both Fe2+ and Mn2+ in controlling transcription at four loci, collectively known as the peroxide regulon (Bsat et al., 1998
). PerR-repressed genes encode a variety of oxidative stress response proteins, including the vegetative cell catalase, alkyl hydroperoxide reductase, haem biosynthetic enzymes and a protective DNA-binding protein, MrgA.
Recent studies with L. plantarum have provided further evidence for an important role of Mn2+-sensing and signalling in bacteria. Expression of not only the P-type ATPase MntA, but also of two glycolytic enzymes, enolase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is repressed in Mn2+-rich medium (Hao et al., 1999 ). Surface-bound enolase and GAPDH have been shown to bind human tissue proteins in a variety of organisms, and in group A streptococci they are implicated in the ability of the bacteria to modulate host cell functions (Pancholi & Fischetti, 1998
). It is tempting to speculate, therefore, that Mn2+ concentrations might influence expression of surface proteins that are relevant for colonization or virulence.
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Mn2+ homeostasis and virulence |
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Roles for the bacterial Nramps in virulence are less well established. These proteins might be necessary for the acquisition of divalent cations by bacteria within phagosomes during chronic infections. However, disruption of mntH in Sal. typhimurium, while delaying mortality in a mouse model, does not affect survival of bacteria within macrophages (Kehres et al., 2000 ). There is, on the other hand, a direct correlation between Mn2+ homeostasis and sensitivity of bacteria to oxidative stress. Inactivation of the Nramp transporter genes in B. subtilis, E. coli or Sal. typhimurium enhances the sensitivities of these bacteria to H2O2 compared with the corresponding wild-type strains (Kehres et al., 2000
; Que & Helmann, 2000
). In Strep. gordonii, the activity of MnSOD is 50% reduced in scaA or scaC mutants that lack the functional ABC-type Mn2+ transporter (N. S. Jakubovics, A. W. Smith & H. F. Jenkinson, unpublished). Taken collectively, these recent data indicate that bacterial systems for acquiring Mn2+ are crucial for protection against reactive oxygen. Since ROS play such an important role in host defence against bacterial infection (Miller & Britigan, 1997
), it is logical to hypothesize that an essential function of Mn2+ sequestration by infecting bacteria is to activate defence systems against both externally and internally derived ROS.
A model for the role of Mn2+ homeostasis in the pathogenesis of streptococcal infections is shown in Fig. 2. The main features of this proposal centre on the mechanisms by which streptococci are able to resist the toxic effects of ROS. Exogenous
is probably detoxified by cell-surface MnSOD (Gerlach et al., 1998
). Internal ROS are produced following diffusion of molecular oxygen into bacterial cells from the bloodstream. H2O2 is generated intracellularly predominantly by the activities of pyruvate oxidase (Spx; Pericone et al., 2000
) and other oxidases, which also generate
(Fig. 2
). The major enzyme capable of detoxifying
in streptococci is MnSOD. Since streptococci lack catalase, most H2O2 generated by oxidases and MnSOD is released by the cells, causing haemolysis or tissue damage (Barnard & Stinson, 1996
). Internal protection against H2O2 is afforded by peroxidases such as thiol peroxidase (Tpx), glutathione peroxidase (Gpo) or alkyl hydroperoxide reductase (AhpC) (Kolenbrander et al., 1998
; King et al., 2000
). Intracellular Mn2+ may directly protect against the damaging effects of H2O2 (Kehres et et al., 2000
). For Mn2+ homeostasis to combat oxidative stress, it is thought that streptococci possess at least three Mn2+ transport systems (Fig. 2
). The primary transporter under Mn2+-restricted conditions is postulated to be an ABC-type permease with high specificity for Mn2+. A second transporter, inhibitable by Zn2+ (Kolenbrander et al., 1998
), may correspond to the Adc permease identified in Strep. pneumoniae (Dintilhac et al., 1997
). A third transporter is likely to be an Nramp-like protein, the gene for which is present in Strep. gordonii (N. S. Jakubovics, A. W. Smith & H. F. Jenkinson, unpublished) and also present within the Strep. mutans genome (http://www.genome.ou.edu/smutans). In B. subtilis, activity of the Nramp transporter (MntH) system protects against H2O2 (Que & Helmann, 2000
), while Nramp transporters from E. coli and Sal. typhimurium are upregulated in response to H2O2 (Kehres et al., 2000
). Therefore, future characterization of streptococcal Nramps will allow the pathways for Mn2+ homeostasis and oxidative stress resistance in these organisms to be firmly established.
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Future perspectives |
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In the immediate future, it will be interesting to identify other Mn2+ transporters that are related to the P-type ATPase of L. plantarum, which has an unusually high capacity for Mn2+ import (Hao et al., 1999 ). Also, the discovery of Nramp transporters in bacteria has underscored the similarities between prokaryotic and eukaryotic systems for essential cation uptake. Determining the relative significance of multiple Mn2+ import systems in homeostasis in individual species presents a major challenge for future research. Significantly, the observation that Mn2+ acquisition by bacteria is linked to virulence in the host suggests that Mn2+ transport is a potential new therapeutic target for control of bacterial infection.
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ACKNOWLEDGEMENTS |
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