NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Mobley HLT, Mendz GL, Hazell SL, editors. Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press; 2001.

Cover of Helicobacter pylori

Helicobacter pylori: Physiology and Genetics.

Show details

Chapter 29Gene Regulation

, , and .

Department of Medical Microbiology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The NetherlandsDepartment of Gastroenterology and Hepatology, Dijkzigt University Hospital, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands

Helicobacter pylori is thought to experience little or no competition from other microorganisms in its gastric niche. Furthermore, the gastric mucosa can be regarded as relatively stable, requiring only a low degree of short-term adaptability of the bacterium to adjust to environmental changes. In accordance with this view, only few regulatory functions are apparent in the genome sequences of H. pylori, as compared to other gram-negative bacteria (2, 16). For example, the number of two-component regulatory systems, which are designed to respond to environmental changes on the transcriptional level, is significantly lower in H. pylori than in Escherichia coli (8, 47, 90, 113, 123). Haemophilus influenzae has a similar number of two-component regulatory proteins (44), while Campylobacter jejuni, which is closely related to H. pylori and has a similarly sized genome, seems to have a somewhat broader repertoire (97). These differences probably reflect the variability in the complexity and numbers of environments encountered by each of these bacterial species.

Only four H. pylori proteins have a perfect match to helix-turn-helix motifs, which are characteristic of DNA-binding proteins, or more specifically, for transcription factors. These proteins comprise HspR (Table 1); SecA, a component of the general secretory machinery; and two proteins with no database match (HP1124 and HP1349) (123). In contrast, H. influenzae and E. coli have 34 and 148 putative DNA-binding proteins, respectively (16, 44). H. pylori also lacks many typical key regulatory proteins found in other gram-negative bacteria, such as OxyR, Crp, and FNR (123) that are associated with regulation of gene expression in response to oxidative stress, carbon starvation, and anaerobic conditions, respectively. Similar to its close relative C. jejuni (97), H. pylori contains homologs of sigma factors RpoD (σ70) (10, 126), RpoN (σ54), and FliA (σ28, HP1032) (123) (Table 1), but homologs of stress-related sigma factors RpoH (σ32, heat shock) and RpoS (σ38, stationary phase) are absent (123). Analyses of promoter sequences indicate the presence of σ54- and σ28-regulated promoters upstream several genes of the flagellar machinery (78, 113, 117), but experimental data proving regulation by these sigma factors are not available.

Table 1. Regulators of H. pylori, their putative functions, and stimuli.

Table 1

Regulators of H. pylori, their putative functions, and stimuli.

However, environmental changes such as varying pH levels, immunological responses, and temperature and nutrient fluctuations due to food intake by the host do occur in the gastric mucus. Therefore, like every other microorganism, H. pylori has to adapt to these changes by regulating its gene expression to allow successful and persistent colonization of the stomach. One question that arises is how and to what extent H. pylori regulates the expression of its genes. The absence of some components of important regulatory systems suggests that either regulation is only rudimentarily present or the mechanism of gene regulation works differently in H. pylori and yet unidentified genes play a role in an alternative regulatory network.

Gene Regulation in response to Environmental Factors

Metal-Responsive Gene Regulation

Metal ions such as iron, nickel, and copper are essential elements for all organisms, where they function in basic cell metabolism. Nickel is of particular importance for H. pylori, as the urease enzyme, which is produced in large amounts, requires nickel as a cofactor (see chapter 16). On the other hand, metal ions are potentially toxic and catalyze the formation of reactive oxygen metabolites, such as superoxide and hydroxyl radicals (110). Therefore, it is essential for bacteria to maintain the balance between transport, utilization, and storage of metal ions. In these processes, the regulation of expression of genes involved is of utmost importance.

Ferric uptake regulator

The availability of extracellular iron in host tissues is usually restricted, resulting in a nonspecific host-defense mechanism against pathogens. Pathogenic bacteria often use this iron-restriction as an environmental signal for the coordinate expression of virulence genes (39). In many bacteria, the ferric uptake regulator (Fur) plays a pivotal role in this regulation (3, 20, 39, 131, 137). Fur controls iron homeostasis and is one of the main regulators of iron-acquisition systems. In the presence of its corepressor iron (Fe [II]), the Fur protein forms a dimer and binds to specific sequences in its target promoters. When iron is abundant, the transcription of these Fur-regulated genes is blocked by the binding of Fur.

H. pylori is able to regulate gene expression in response to environmental iron availability. The expression of several proteins was shown to be induced by iron restriction (129), including several outer membrane proteins (68, 69, 138), vacuolating cytotoxin (vacA), and Fur itself (120). In contrast, fumarate reductase (frdCAB), an enzyme requiring iron as a cofactor, and the iron-storage protein ferritin (pfr) are downregulated on the transcriptional level by low iron concentrations (12, 34). A Fur homolog was identified in the H. pylori genome (13, 14, 123) (Table 1) and repressed the transcription of some of the H. pylori putative iron-uptake systems fecA and frpB in the presence of iron (129) (see also chapter 17) (Fig. 1). H. pylori Fur has some features that are distinct from other eubacterial Fur homologs, as it is involved in the repression of ferritin transcription under low instead of high iron concentrations (12) (Fig. 1). Induction of ferritin in response to high iron concentrations is independent of Fur (12). These findings suggest that Fur is able to operate without its corepressor iron. In support of this hypothesis, high concentrations of nickel, zinc, copper, and manganese repress ferritin synthesis, and this regulation is Fur dependent (12). Additionally, Fur is involved in nickel-induced urease expression (130) (Fig. 1). These data indicate that metals other than Fe(II) possibly act as cofactors of Fur, enabling regulation of gene expression in the absence of iron.

Figure 1. The H.

Figure 1

The H. pylori ferric uptake regulator homolog (Fur) as a putative global regulator. Fur is thought to be involved in a range of processes in H. pylori, depicted in boxes, and responds to a variety of environmental stimuli, indicated above the arrows. (more...)

Other metal-responsive regulators

Little is known about metal-responsive regulators in H. pylori other than Fur. Copper induction of a stress-responsive operon containing the copA and copP genes, encoding proteins involved in copper transport, was found (9), but the mechanism responsible for this regulation is not known. Furthermore, a NikR-like transcriptional repressor of the ribbon-helix-helix family (25, 32) has recently been identified in H. pylori (Table 1). In E. coli, NikR represses the nikABCDE operon, encoding a nickel ABC-transporter system, in response to high intracellular nickel concentrations (32). H. pylori does have some of the NikABCDE homologs (59), as well as a homolog of a HoxN-type nickel permease, NixA (91), a high-affinity nickel transporter, essential for high-level urease activity in H. pylori (6, 91). There are, however, no reports on nickel-dependent regulation of NixA or Nik homologs in H. pylori, and, so far, the function of the NikR homolog in H. pylori remains unclear.

Acid-Responsive Gene Regulation

It is generally accepted that low pH induces a global stress response and regulates the expression of virulence genes in several bacterial species (42, 76, 77, 80). For example, the alternative sigma factor RpoS is an important regulator of acid tolerance (48, 76, 77, 111). Additional regulators that play a role in the acid response are Fur, Ada, and the two-component regulatory system PhoP/PhoQ of Salmonella enterica serovar Typhimurium (7, 46, 53).

As H. pylori persistently colonizes the gastric environment, it is likely that acid-responsive systems, regulating the expression of acid-resistance and virulence genes, are present. Surprisingly, only a relatively limited number of studies on acid-induced gene expression in H. pylori are available. H. pylori lacks orthologs of most of the acid-induced genes of E. coli or S. enterica serovar Typhimurium such as amino acid carboxylases and formate hydrogen lyase (123). However, exposure to acid leads to a change in protein composition (72, 85), indicating that an acid-inducible response is present in H. pylori. Indeed, the expression of several H. pylori genes is regulated in response to pH, including cagA (cytotoxin-associated gene A and marker of the pathogenicity island), vacA (vacuolating cytotoxin) (72), picB (also known as cagE, gene associated with interleukin-8 induction), urease structural and accessory genes (1, 74), the lipopolysaccharide (LPS)-associated gene, wbcJ (86), the heat shock proteins (HSPs) DnaK and GroEL (63, 66, 67), and the serine protease HtrA (72). Most of these genes are related to virulence, supporting the hypothesis that H. pylori regulates virulence genes in response to pH. It is also not surprising that urease activity is controlled by pH. High urease activity under acidic conditions is essential for bacterial survival, though under neutral conditions it is lethal to the bacterium (26). Acid induction of HSPs, which has also been demonstrated for E. coli (62), may be of particular importance for H. pylori. The HSPs DnaK and GroELS promote urease activity and epithelial cell adhesion, and acid induction of such proteins may be important in establishing colonization (63, 66, 72a).

Little is known about the regulatory mechanisms involved in acid-responsive gene expression in H. pylori. Of the above-mentioned acid-tolerance-associated regulators, only Fur is present in H. pylori (14, 123). An H. pylori fur mutant was clearly affected in its acid resistance, being unable to grow at a pH of 5.5 or to survive acid shock (17). A role for Fur in acid-responsive regulation is likely (Fig. 1), but this has not yet been reported.

Oxidative Stress-Induced Regulation

The bacterial enzymes superoxide dismutase (SOD) and catalase are important factors in the defense against oxidative stress. In most gram-negative bacteria, a large number of proteins are induced in response to oxidative stress (51, 116, 133). These global responses involve the soxRS regulon, which is activated by the presence of reactive oxygen metabolites and results in the expression of a wide variety of enzymes that includes an SOD (28, 95). Additional factors that are involved in the oxidative stress response are RpoS (42, 95), LexA, a repressor of SOS DNA damage repair proteins (116, 132), OxyR, Fur, and PerR (21, 37, 94, 128, 144).

As H. pylori has to cope with reactive oxygen metabolites at the inflamed gastric mucosal surface, oxidative stress response mechanisms are likely to be present (see also chapter 15). The activity of the H. pylori catalase (katA) (56, 96) is affected in vitro by the presence of serum or blood (56), and a regulator that directs the expression of the katA gene may be present (83). In contrast to E. coli SOD, the expression of H. pylori SOD is not regulated in response to oxidative stress (15). H. pylori lacks SoxR, SoxS, OxyR, RpoS, LexA, and PerR homologs (123), and until now, no factors involved in the regulation of the oxidative stress response have been presented. A potential binding site for Fur is present upstream of the katA gene (96) and suggests a possible function of Fur in the regulation of catalase expression (Fig. 1).

Regulation by Temperature and Osmotic Stress

HSPs function as molecular chaperones in both normal and stressed cells (61) and play an important role in protecting the cell against damage imposed by heat and other stresses (62, 82). The expression of bacterial HSPs is usually regulated by temperature up-shifts and can be controlled by both positive and negative regulatory mechanisms. Positive control of chaperone transcription operates through alternative sigma factors, in particular RpoII (23), and requires specific heat shock promoters. Negative control is mediated by repressor proteins such as HspR in Streptomyces species and HrcA in Bacillus subtilis (22, 49, 50, 93, 108).

An upshift in osmolarity has a global effect on E. coli gene expression, regulating several uptake and transport systems that can restore turgor pressure (29). Sigma factor RpoS seems to play a key role in osmotic stress control, but two-component regulatory systems such as EnvZ/OmpR and KdpD/KdpE are also involved (60).

Whereas osmotic pressure in the gastric environment varies significantly and H. pylori is expected to respond adequately to osmotic stress, the relevance of a temperature shift-induced expression for H. pylori is less clear. Temporary temperature changes in the gastric environment due to food intake by the host could impose heat stress on H. pylori. Furthermore, a change in temperature could constitute an important signal for the bacterium that it has either entered or left the host, leading to specific regulation of genes. The H. pylori genome contains genes encoding the HSP homologs GroEL, GroES, DnaK, DnaJ, GrpE, HtpG, and CbpA (67, 73, 123) (Fig. 2), and most of these genes are induced by a temperature upshift (9, 34, 64, 141, 143). GroEL, GroES, and DnaK have been shown to play a role in regulating urease activity and epithelial cell adhesion (40, 118, 140).

Figure 2. Regulation of H.

Figure 2

Regulation of H. pylori chaperone genes. Structural organization of the chaperone genes is according to Tomb et al. (123). Solid arrows indicate regulation by HspR confirmed by experimental data of Spohn and Scarlato (114). Dashed arrows indicate putative (more...)

Although H. pylori lacks heat shock sigma factor RpoH, homologs of the repressor proteins HspR and HrcA have been identified (114, 123) (Table 1). These repressors bind to the cis-acting elements HAIR (HspR-associated inverted repeat) and CIRCE (controlling inverted repeat of chaperone expression) located in the upstream regulatory regions of chaperone genes (49, 50, 93). Both elements are associated with the σ70-transcribed classical housekeeping promoters. The genome sequences of H. pylori revealed the presence of HAIR boxes upstream of various HSP genes (49). As in Streptomyces (22), H. pylori HspR represses the transcription of the cbpA-hspR-HP1026 and hrcA-grpE-dnaK operons (114) (Fig. 2). Unlike Streptomyces, HspR represses the groESL operon in H. pylori (114). The promoter regions of the cbpA and the groELS operons contained a HAIR element, which was bound by HspR. In the case of the hrcA-operon, HspR bound to a sequence with no distinct homology to HAIR. HrcA itself may play a role in the regulation of its operon, as its promoter region contains a CIRCE-like element (114), but this was not further investigated.

While in other bacteria HspR responds to temperature stimuli, repression of the cbpA and groELS operons by the H. pylori HspR was mediated by osmotic stress (114) (Fig. 2). It was speculated that the difference between the C-terminal amino acid sequences of H. pylori HspR and the heat shock-responsive Streptomyces coelicolor HspR would account for the fact that H. pylori HspR reacts to osmotic rather than temperature-related stimuli. In other bacteria, RpoS plays an important role in transcriptional regulation in response to osmotic stress (60). As RpoS is not present in H. pylori, it could be speculated that HspR performs the task of osmotic stress response regulator. In addition, H. pylori contains three response regulators (HP0166, HP1043, and HP1365) of the OmpR family (8), a family with members that are involved in osmotic stress control (103). None of these have been investigated for their role in the osmotic stress response in H. pylori.

There have been conflicting reports regarding the temperature control of HSPs in H. pylori. Whereas Spohn and Scarlato (114) did not find temperature-dependent HSP expression, several other studies have demonstrated a clear heat induction of groELS, dnaK as well as dnaJ, and various other genes (9, 34, 64, 141, 143). This shows that H. pylori is capable of mounting a heat shock response, and although no direct evidence has been presented that HspR or HrcA affects gene expression in response to temperature stimuli in H. pylori, this is likely to be the case. Furthermore, a subset of the HSP genes, among which is the dnaJ gene (64), does not have an obvious HAIR or CIRCE element in the regulatory region, suggesting that alternative regulatory mechanisms must be present that respond to temperature stimuli.

Regulation by Bacterial Density

Quorum sensing is a mechanism by which bacteria sense and respond to their own population density by means of signaling molecules, called autoinducers (31). Quorum sensing affects the expression of many cellular processes, including that of virulence genes (112, 136). For example, in Vibrio harveyi, the expression of bioluminescence proteins encoded by the lux operon is affected by bacterial density through quorum sensing (119). Here, autoinducers, AI-1 and AI-2, interact with their respective cognate sensor proteins LuxN and LuxQ. This interaction initiates a signal transduction cascade converging on the response regulator LuxO, resulting in derepression of the lux operon. The positive regulator LuxR is also required for the activation of the lux operon, while the LuxS protein, which is present in many bacterial species (119), is responsible for the synthesis of AI-2.

A LuxS homolog is present in H. pylori and was shown to be involved in the production of AI-2 activity, in a similar manner as in V. harveyi (45, 71). The in vitro expression of motility, urease activity, Cag-mediated IL-8 induction, or vacuolization was not affected in a luxS mutant, so a possible role of this quorum-sensing pathway in the regulation of virulence genes could not be established (71). Also, no detectable differences in whole-cell protein expression were found between wild-type H. pylori and the luxS mutant. Further homologs of the AI-2 system of quorum sensing in V. harveyi have not been identified in H. pylori until now.

Regulation of Motility and Chemotaxis

Motility and chemotaxis are important virulence factors of H. pylori and are essential for colonization of the stomach (38; see chapter 21). The mechanisms regulating the expression of flagellar genes and the chemotactic response in H. pylori involve the FlgR-HP0244 and the CheA-CheY two-component regulatory systems (8, 47, 113). Two-component regulatory systems enable bacteria to regulate their cellular functions in response to a variety of environmental stimuli (Fig. 3). The two systems involved in the regulation of H. pylori motility and chemotaxis are part of only four cognate histidine kinase-response regulator pairs that have so far been identified in H. pylori (Fig. 3). An additional regulator protein, FlbA, is involved in regulation of motility, demonstrating the importance for the bacterium to regulate these virulence traits (38).

Figure 3. Schematic representation of a two-component signal transduction system.

Figure 3

Schematic representation of a two-component signal transduction system. Signal transduction occurs through autophosphorylation of the histidine kinase sensor (HKS) upon binding of a ligand from the environment. The subsequent transfer of the phosphoryl (more...)

Regulation of Flagellar Gene Expression by FlbA and FlgR

The flagellar apparatus of E. coli and S. enterica serovar Typhimurium consists of more than 40 genes, which are expressed in a coordinate manner (81). Early genes are master regulator proteins, such as flhCD and flgM, that direct the expression of intermediate genes (flagellar hook and basal body) and late flagellar genes (structural genes). The LcrD/FlbF and the NtrC (NR-I) families of regulator proteins contain members that are involved in the regulation of flagellar biogenesis (8, 52, 87, 88, 101, 113).

FlbA

Although homologs of master regulators FlgM and FlhCD are absent, H. pylori does contain an FlbA homolog, a member of the LcrD/FlbF family. FlbA is a cytoplasmic membrane-bound protein and does not contain DNA-binding motifs or motifs suggestive of a two-component regulatory system (87, 104), but possibly functions as a signal transducer. The H. pylori FlbA is involved in the coordinated regulation of H. pylori flagellar biogenesis (107) (Table 1). An H. pylori flbA mutant was nonmotile, did not transcribe the structural flaA and flaB genes, and showed reduced transcription of the flgE gene, which encodes a flagellar hook protein. This indicates that FlbA is a positive regulator of both flaA and flaB transcription and less rigidly of flgE transcription (Fig. 4). Preliminary results indicated that growth phase affects expression of flagellar proteins FlaA, FlaB, and FlgE and that FlbA could be responsible for coordinating growth phase-dependent regulation (107). FlbA has also been shown to positively affect adherence of H. pylori to primary gastric cells (27) and to inhibit urease expression in an E. coli strain, containing the H. pylori urease gene cluster and the nixA gene on a plasmid (84). These data support a possible function of H. pylori FlbA in the regulation of virulence-associated proteins. The mode of action of H. pylori FlbA has, however, not yet been elucidated.

Figure 4. Schematic representation of regulation of flagellar biogenesis.

Figure 4

Schematic representation of regulation of flagellar biogenesis. For explanation see text.

FlgR

H. pylori FlgR is homologous to regulators of the NtrC (NR-I) family (113) (Table 1) that usually bind enhancer-like DNA sequences located far upstream of σ54 promoters and activate σ54-regulated transcription (75). FlgR shows a high degree of similarity to FlrC of Vibrio cholerae and FlbD of Caulobacter crescentus, proteins involved in regulation of flagellar biosynthesis (8, 113). FlgR is the response regulator of a two-component regulatory system together with its cognate histidine kinase sensor HP0244 (8) (Fig. 3). HP0244 has similarity to E. coli NtrB (41) and is located in the cytoplasm. It is likely that an additional sensory transmembrane protein is present that transduces a yet unidentified environmental signal to HP0244.

FlgR is required for H. pylori motility and flagellar synthesis and transcribes the σ54-regulated intermediate and late flagellar genes, encoding the basal-body and hook proteins (8, 113) (Fig. 4). This corresponds with part of the flagellar synthesis process in Caulobacter sp., where σ54 and its cognate transcriptional activator FlbD transcribe the late basal body and hook genes (139). However, the flaA gene is transcribed from a σ28 promoter (78) and is repressed by FlgR (113) (Fig. 4), which is more in line with the flagellar biogenesis as it occurs in genera of the Enterobacteriaceae.

The FlgR-dependent transcription of the H. pylori flaB promoter appears to be affected by changes in DNA topology (113), a feature that has been previously described for NtrC in E. coli (19). Possibly, the FlgR-controlled expression of the H. pylori flaB promoter is dependent on its supercoiled state, which, in turn, may depend on environmental conditions (36, 113).

Regulation of Chemotaxis: the CheA-CheY System

The CheA-CheY two-component system, regulating the chemotactic response, has been studied extensively in E. coli and S. entercia serovar Typhimurium (115). The binding of repellents from the environment to membrane-bound methyl-accepting chemoreceptor proteins (MCPs) triggers an intracellular phosphorylation cascade (Fig. 5). Phosphorylation of the CheA histidine-kinase sensor results in the activation of the CheY response regulator. Unlike other response regulators, CheY has no DNA-binding domain and does not act as a transcriptional activator. Instead, when activated, it interacts directly with FliM in the flagellar motor-switch complex, causing a clockwise rotation of the flagella that results in a tumbling motion of the cell (Fig. 5). Attractants have the opposite effect and inhibit the phosphorylation cascade through methylation of the MCPs by the CheR protein. This results in counterclockwise rotation of the flagella and smooth swimming. In addition, the CheZ protein is able to terminate the chemotactic response by accelerating the dephosphorylation of the CheY response regulator (Fig. 5).

Figure 5. Schematic representation of the CheA-CheY two-component system for regulation of the chemotactic response.

Figure 5

Schematic representation of the CheA-CheY two-component system for regulation of the chemotactic response. Putative H. pylori homologs are written in the lower parts of the respective boxes. For further explanation see text.

H. pylori shows a chemotactic response to gastric mucin, urea, and bicarbonate (47, 89). Homologs of MCPs, CheA, and CheY (cheY1) have been identified, but CheZ and CheR homologs have not been found (9, 47, 123). An additional copy of the CheY gene, cheY2, is fused to the cheA gene (47). H. pylori mutants of cheA and cheY1 have a strongly impaired motility, show a reduced chemotactic response to porcine gastric mucin in vitro, and are unable to colonize mice (9, 47). CheY2 probably exercises the function of the classical CheY response regulator, as a mutation in cheY2 reduces tumbling motion (47). Similar to E. coli, CheY2 presumably is phosphorylated by CheA and interacts with the flagellar motor switch, which results in a tumbling motion (Fig. 5). The other copy of CheY (cheY1) possibly replaces the CheZ protein in H. pylori (47). Interestingly, this cheY1 gene is part of an operon that is induced by temperature upshift and increased copper concentration (9). This operon also contains the hsm gene, encoding a putative HSP with methyltransferase activity, which may fulfill the function of the lacking CheR homolog (9) (Fig. 5). The induction of CheY1 and Hsm may promote the transition from tumbling to smooth and straight swimming, an important adaptive stress response advantageous in coping with harmful conditions.

Phase Variation

Phase variation is the apparently random on-and off-switching of gene expression, and this mechanism of gene regulation is often encountered in bacterial surface-exposed structures such as flagella, adhesins, and LPS. Phase variation plays an important role in bacterial pathogenesis and virulence by generating antigenic variation and environmental adaptation (30, 54, 58, 65, 79, 127). Various mechanisms of phase variation have been studied in a range of bacterial species (18, 92, 105, 125). One common mechanism is slipped-strand DNA mispairing, which is mediated through short sequence nucleotide repeats present in the coding region of a gene or in the promoter (54, 65, 124). During replication, slippage of the DNA polymerase may lead to a change in the number of repeat units. When the repeats are present in an open reading frame, slippage can lead to a frameshift, which results in the translation of a truncated protein (54, 92). Alternatively, when the repeats are present in a promoter, promoter function is affected and phase variation occurs at the transcriptional level (11, 105, 125).

A large number of multiple nucleotide repeats, present in open reading frames and 5′ intergenic regions, have been found in the genome of H. pylori (2, 43, 106, 123), indicating that H. pylori has a significant potential for phase variation through slipped-strand mispairing. Phase variation affecting promoter function has not been demonstrated yet, but several H. pylori genes have been identified that display phase variation through slippage in repeats in their coding regions. These include LPS synthesis genes, in particular the α1,2- and α3-fucosyl transferases (4, 5, 134), the hopZ gene, encoding a porin and possibly involved in adhesion (98), and the oipA gene, a proinflammatory outer membrane protein (142). Phase variation of the fliP gene, encoding a flagellar basal-body protein, was shown to shut down flagellar assembly and switch off motility (70) (Fig. 4). Furthermore, one study demonstrated that the C-terminal part of the HP0165 histidine kinase sensor varied between different H. pylori strains due to a frameshift in a C-tract (8). One could speculate that in vivo this variability could affect the signal transduction process and prevent regulation of target genes in the sequence variants. It was, however, not investigated whether phase variation occurred within one single strain.

A type III restriction-methylation (R-M) system was found to display phase variation both through slipped-strand mispairing and through a yet unidentified transcriptional mechanism (33). This demonstrates that phase variation at the transcriptional level also exists in H. pylori. DNA repeats have been shown to be present in several R-M genes of H. pylori (2, 43, 106, 123), so that phase variation through slipped-strand mispairing is likely to occur in these genes. In many bacteria, DNA methylases play an important role in the regulation of cell cycle events and virulence gene expression (18, 57), and it has recently been suggested that the H. pylori iceA1-hpyIM R-M system, which is thought to be associated with increased virulence (35, 99), could play a role in gene regulation (35). The abundance of R-M genes in H. pylori suggests a specific role in pathogenesis, in which regulation of virulence genes by DNA methylation could be involved. Phase variation in methylase genes can provide an extra dimension to gene regulation by H. pylori.

Repetitive DNA can also play a role in another mechanism that has been suggested to mediate antigenic variation: mosaic formation (16, 123). The large H. pylori family of outer membrane proteins consists of closely related genes, which potentially are able to recombine leading to mosaic organization, as described for Mycoplasma genitalium (100). Repetitive DNA is generally known to play an important role in these recombinational events (100, 109), but no data are currently available that demonstrate the occurrence of similar events in H. pylori.

H. pylori has a relatively small genome; therefore, phase variation mediated by DNA repeats is probably a more efficient way to respond and adapt to environmental change than harboring and expressing regulatory genes and intricate regulatory networks.

Other Regulatory Systems

Apart from the CheA-CheY and FlgR-HP0244 systems involved in chemotaxis and motility, two additional two-component protein homolog pairs were found in H. pylori, namely the HP0165 histidine kinase sensor and HP0166 response regulator, and the HP1364 histidine kinase sensor and HP1365 response regulator (8) (Table 1). Both response regulators show homology to the OmpR family of osmoregulatory proteins. It was suggested that the HP0166 response regulator is essential, as the corresponding gene could not be disrupted. Furthermore, the HP0165 histidine kinase sensor may be subject to additional regulation by phase variation (8). For the two remaining response regulator homologs, HP1021 and HP1043, no cognate histidine kinase sensors were identified (8) (Table 1). HP1043 is grouped in the OmpR family, and homologs of both response regulators were recently identified in the genome sequence of C. jejuni (97). Interestingly, the receiver domains of HP1021 and HP1043 deviate from the response regulator consensus sequences to such an extent that it is questionable whether they require phosphorylation to exert their function. Their genes could not be mutated (8), indicating that these response regulators are essential for viability of H. pylori. No clues have been found as to what the function is of these regulatory systems and what environmental factors are involved.

Apart from the yet unidentified response regulators, several homologs of transcriptional regulators are present in H. pylori of which the function is still unknown (123). For example, H. pylori has a homolog of the carbon storage regulator, CsrA. In E. coli and Erwinia spp., CsrA is part of a global regulatory system that regulates stationary-phase genes and central carbon metabolism (102,135).

Other, less common mechanisms have been proposed to play a role in H. pylori gene regulation. For example, read-through from a promoter of an upstream gene or operon into a downstream locus has been demonstrated for urease genes (1) and for the iceA1 gene (35). Here, the locus is transcribed from its own promoter, while read-through from the upstream promoter is able to modulate its transcriptional level. Also, posttranscriptional regulation of gene expression has been described for H. pylori. Recent work has shown that H. pylori regulates the expression of the urease operon in response to pH by means of differential mRNA decay (1). H. pylori contains homologs of several enzymes proposed in mRNA decay, such as RNase III (rnc), polynucleotide phosphorylase (PNPase, pnp), RNA helicase (deaD), and poly(A) polymerase (papS) (123), which are likely to play a role in this form of gene regulation.

Conclusions

Even though components of important regulatory systems such as RpoS, which are essential for the general stress response in many bacteria, seem to be absent in H. pylori, this bacterium is clearly capable of mounting such a response. Two H. pylori genome sequences are currently available (2, 123), but insight into how gene expression is regulated is still limited. However, studies on several classical regulatory systems and on phase variation are slowly beginning to elucidate some aspects of gene regulation in H. pylori.

Because H. pylori shows responses to various environmental stresses for which the classical global regulators are absent, H. pylori must have alternative, yet unrecognized regulatory systems. One possible explanation is that the few classical transcriptional regulators that are present in H. pylori may provide additional functions, thereby compensating for lack of some regulators. The repressor HspR and possibly HrcA may constitute alternatives for the heat shock sigma factor σ32, as seems to be the case in C. jejuni (121, 122). The absence of the master regulator RpoS (42, 60, 76) may be compensated for by alternative regulator proteins such as Fur and HspR (12, 17, 114). In addition, it becomes more clear that phase variation plays an important role in H. pylori gene regulation, whereas mechanisms such as DNA methylation and supercoiling should be considered as potential factors affecting H. pylori gene transcription.

Obviously, much work remains to be done to elucidate the regulatory mechanisms that are involved in H. pylori gene expression. The application of novel techniques and approaches such as DNA microarrays and proteomics will hopefully lead to the identification of additional environmentally regulated genes, while further characterization of the two-component systems will give insight into how H. pylori responds to its environment and is able to cause disease. Surprisingly little is known about the in vivo relevance of gene regulation in H. pylori. The use of in vitro systems simulating in vivo conditions remains inadequate, so in vivo studies are required using techniques such as IVET (in vivo expression technology) or IVIAT (in vivo induced antigen technology) techniques (24, 55).

All bacteria, including H. pylori, sense their environment and respond to changing conditions by adjusting the level of expression of certain genes. Perhaps the paucity of regulatory functions in H. pylori makes the field of gene regulation an even more important subject for research. Targeting a regulatory pathway in such a background renders it more likely that vaccines or therapies will be efficient, as redundant pathways may not be present.

Acknowledgments

This work was financially supported by the Research Stimulation Fund (USF) of the Vrije Universiteit, Amsterdam, The Netherlands, and the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO grant 901-14-206).

References

1.
Akada J. K., Shirai M., Takeuchi H., Tsuda M., Nakazawa T. Identification of the urease operon in Helicobacter pylori and its control by mRNA decay in response to pH. Mol. Microbiol. 2000;36:1071–1084. [PubMed: 10844692]
2.
Alm R. A., Ling L. S., Moir D. T., King B. L., Brown E. D., Doig P. C., Smith D. R., Noonan B., Guild B. C., de-Jonge B. L., Carmel G., Tummino P. J., Caruso A., Uria-Nickelsen M., Mills D. M., Ives C., Gibson R., Merberg D., Mills S. D., Jiang Q., Taylor D. E., Vovis G. F., Trust T. J. Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori. Nature. 1999;397:176–180. [PubMed: 9923682]
3.
Andrews S. C. Iron storage in bacteria. Adv. Microb. Physiol. 1998;40:281–351. [PubMed: 9889981]
4.
Appelmelk B. J., Martin S. L., Monteiro M. A., Clayton C. A., McColm A. A., Zheng P., Verboom T., Maaskant J. J., van den Eijnden D. H., Hokke C. H., Perry M. B., Vandenbroucke-Grauls C. M., Kusters J. G. Phase variation in Helicobacter pylori lipopolysaccharide. due to changes in the lengths of poly(C) tracts in alpha3-fucosyltransferase genes. Infect. Immun. 1999;67:5361–5366. [PMC free article: PMC96892] [PubMed: 10496917]
5.
Appelmelk B. J., Shiberu B., Trinks C., Tapsi N., Zheng P. Y., Verboom T., Maaskant J., Hokke C. H., Schiphorst W. E., Blanchard D., Simoons-Smit I. M., van den Eijnden D. H., Vandenbroucke-Grauls C. M. Phase variation in Helicobacter pylori lipopolysaccharide. Infect. Immun. 1998;66:70–76. [PMC free article: PMC107860] [PubMed: 9423841]
6.
Bauerfeind P., Garner R. M., Mobley L. T. Allelic exchange mutagenesis of nixA in Helicobacter pylori results in reduced nickel transport and urease activity. Infect. Immun. 1996;64:2877–2880. [PMC free article: PMC174160] [PubMed: 8698529]
7.
Bearson B. L., Wilson L., Foster J. W. A low pH-inducible, PhoPQ-dependent acid tolerance response protects Salmonella typhimurium against inorganic acid stress. J. Bacteriol. 1998;180:2409–2417. [PMC free article: PMC107183] [PubMed: 9573193]
8.
Beier D., Frank R. Molecular characterization of two-component systems of Helicobacter pylori. J. Bacteriol. 2000;182:2068–2076. [PMC free article: PMC111253] [PubMed: 10735847]
9.
Beier D., Spohn G., Rappuoli R., Scarlato V. Identification and characterization of an operon of Helicobacter pylori that is involved in motility and stress adaptation. J. Bacteriol. 1997;179:4676–4683. [PMC free article: PMC179311] [PubMed: 9244252]
10.
Beier D., Spohn G., Rappuoli R., Scarlato V. Functional analysis of the Helicobacter pylori principal sigma subunit of RNA polymerase reveals that the spacer region is important for efficient transcription. Mol. Microbiol. 1998;30:121–134. [PubMed: 9786190]
11.
Belland R. J., Morrison S. G., Carlson J. H., Hogan D. M. Promoter strength influences phase variation of neisserial opa genes. Mol. Microbiol. 1997;23:123–135. [PubMed: 9004226]
12.
Bereswill S., Greiner S., van Vliet A. H. M., Waidner B., Fassbinder F., Schiltz E., Kusters J. G., Kist M. Regulation of ferritin-mediated cytoplasmic iron storage by the ferric uptake regulator homolog (Fur) of Helicobacter pylori. J. Bacteriol. 2000;182:5948–5953. [PMC free article: PMC94726] [PubMed: 11029412]
13.
Bereswill S., Lichte F., Greiner S., Waidner B., Fassbinder F., Kist M. The ferric uptake regulator (Fur) homologue of Helicobacter pylori: functional analysis of the coding gene and controlled production of the recombinant protein in Escherichia coli. Med. Microbiol. Immunol. (Berlin) 1999;188:31–40. [PubMed: 10691091]
14.
Bereswill S., Lichte F., Vey T., Fassbinder F., Kist M. Cloning and characterization of the fur gene from Helicobacter pylori. FEMS Microbiol. Lett. 1998;159:193–200. [PubMed: 9503612]
15.
Bereswill S., Neuner O., Strobel S., Kist M. Identification and molecular analysis of superoxide dismutase isoforms in Helicobacter pylori. FEMS Microbiol. Lett. 2000;183:241–245. [PubMed: 10675591]
16.
Berg D. E., Hoffman P. S., Appelmelk B. J., Kusters J. G. The Helicobacter pylori genome sequence: genetic factors for long life in the gastric mucosa. Trends Microbiol. 1997;5:468–474. [PubMed: 9447657]
17.
Bijlsma, J. J. E. 2000. Hp dna and pH. The acid resistance of Helicobacter pylori. Ph.D. thesis. Vrije Universiteit, Amsterdam, The Netherlands.
18.
Blyn L. B., Braaten B. A., Low D. A. Regulation of pap pilin phase variation by a mechanism involving differential dam methylation states. EMBO J. 1990;9:4045–4054. [PMC free article: PMC552177] [PubMed: 2147413]
19.
Brahms G., Brahms S., Magasanik B. A sequence-induced superhelical DNA segment serves as transcriptional enhancer. J. Mol. Biol. 1995;246:35–42. [PubMed: 7853402]
20.
Braun V., Killmann H. Bacterial solutions to the iron-supply problem. Trends Biochem. Sci. 1999;24:104–109. [PubMed: 10203757]
21.
Bsat N., Herbig A., Casillas-Martinez I., Setlow P., Helmann J. D. Bacillus subtilis contains multiple Fur homologues: identification of the iron uptake (Fur) and peroxide regulon (PerR) repressors. Mol. Microbiol. 1998;29:189–198. [PubMed: 9701813]
22.
Bucca G., Hindle Z., Smith C. P. Regulation of the dnaK operon of Streptomyces coelicolor A3(2) is governed by HspR, an autoregulatory repressor protein. J. Bacteriol. 1997;179:5999–6004. [PMC free article: PMC179499] [PubMed: 9324243]
23.
Bukau B. Regulation of the Escherichia coli heat-shock response. Mol. Microbiol. 1993;9:671–680. [PubMed: 7901731]
24.
Chiang S. L., Mekalanos J. J., Holden D. W. In vivo genetic analysis of bacterial virulence. Annu. Rev. Microbiol. 1999;53:129–154. [PubMed: 10547688]
25.
Chivers P. T., Sauer R. T. Regulation of high-affinity nickel uptake in bacteria: Ni2+-dependent interaction of NikR with wild-type and mutant operator sites. J. Biol. Chem. 2000;275:19735–19741. [PubMed: 10787413]
26.
Clyne M., Labigne A., Drumm B. Helicobacter pylori requires an acidic environment to survive in the presence of urea. Infect. Immun. 1995;63:1669–1673. [PMC free article: PMC173208] [PubMed: 7729871]
27.
Clyne M., O'Croinin T., Suerbaum S., Josenhans C., Drumm B. Adherence of isogenic flagellum-negative mutants of Helicobacter pylori and Helicobacter mustelae to human and ferret gastric epithelial cells. Infect. Immun. 2000;68:4335–4339. [PMC free article: PMC101762] [PubMed: 10858255]
28.
Compan I., Touati D. Interaction of six global transcription regulators in expression of manganese superoxide dismutase in Escherichia coli K-12. J. Bacteriol. 1993;175:1687–1696. [PMC free article: PMC203963] [PubMed: 8449876]
29.
Csonka, L. N., and W. Epstein. 1996. Osmoregulation, p. 1210–1223. In F. C. Neidhardt, R. Curtiss III, J. L. Ingraham, E. C. C. Lin, K. B. Low, B. Magasanik, W. S. Reznikoff, M. Riley, M. Schaechter, and H. E. Umbarger (ed.), Escherichia coli and Salmonella: Cellular and Molecular Biology, 2nd ed. ASM Press, Washington, D.C.
30.
Deitsch K. W., Moxon E. R., Wellems T. E. Shared themes of antigenic variation and virulence in bacterial, protozoal, and fungal infections. Microbiol. Mol. Biol. Rev. 1997;61:281–293. [PMC free article: PMC232611] [PubMed: 9293182]
31.
de Kievit T. R., Iglewski B. H. Bacterial quorum sensing in pathogenic relationships. Infect. Immun. 2000;68:4839–4849. [PMC free article: PMC101676] [PubMed: 10948095]
32.
De Pina K., Desjardin V., Mandrand-Berthelot M. A., Giordano G., Wu L. F. Isolation and characterization of the nikR gene encoding a nickel-responsive regulator in Escherichia coli. J. Bacteriol. 1999;181:670–674. [PMC free article: PMC93426] [PubMed: 9882686]
33.
de Vries N., Duinsbergen D., Kuipers E. J., Wiesenekker P., Vandenbroucke-Grauls C. M. J. E., Kusters J. G. Phase variation in a type III restriction-modification system of Helicobacter pylori. Gastroenterology. 2000;118(Part 1, Suppl. 2):A736.
34.
de Vries, N., E. J. Kuipers, N. E. Kramer, A. H. M. van Vliet, J. J. E. Bijlsma, M. Kist, S. Bereswill, C. M. J. E. Vandenbroucke-Grauls, and J. G. Kusters. Identification of environmental stress-regulated genes in Helicobacter pylori by a lacZ reporter gene fusion system. Submitted for publication. [PubMed: 11843962]
35.
Donahue J. P., Peek R. M., Van Doorn L. J., Thompson S. A., Xu Q., Blaser M. J., Miller G. G. Analysis of iceA1 transcription in Helicobacter pylori. Helicobacter. 2000;5:1–12. [PMC free article: PMC2779704] [PubMed: 10672045]
36.
Drlica K. Control of bacterial DNA supercoiling. Mol. Microbiol. 1992;6:425–433. [PubMed: 1313943]
37.
Dubrac S., Touati D. Fur positive regulation of iron superoxide dismutase in Escherichia coli: functional analysis of the sodB promoter. J. Bacteriol. 2000;182:3802–3808. [PMC free article: PMC94553] [PubMed: 10850997]
38.
Eaton K. A., Suerbaum S., Josenhans C., Krakowka S. Colonization of gnotobiotic piglets by Helicobacter pylori deficient in two flagellin genes. Infect. Immun. 1996;64:2445–2448. [PMC free article: PMC174096] [PubMed: 8698465]
39.
Escolar L., Perez-Martin J., de Lorenzo V. Opening the iron-box: transcriptional metalloregulation by the Fur protein. J. Bacteriol. 1999;181:6223–6229. [PMC free article: PMC103753] [PubMed: 10515908]
40.
Evans D. J., Evans D. G., Engstrand L., Graham D. Y. Urease-associated heat shock protein of Helicobacter pylori. Infect. Immun. 1992;60:2125–2127. [PMC free article: PMC257126] [PubMed: 1348725]
41.
Fabret C., Feher V. A., Hoch J. A. Two-component signal transduction in Bacillus subtilis: how one organism sees its world. J. Bacteriol. 1999;181:1983. [PMC free article: PMC93607] [PubMed: 10094672]
42.
Fang F. C., Libby S. J., Buchmeier N. A., Loewen P. C., Switala J., Harwood J., Guiney D. G. The alternative sigma factor katF (rpoS) regulates Salmonella virulence. Proc. Natl. Acad. Sci. USA. 1992;89:11978–11982. [PMC free article: PMC50681] [PubMed: 1465428]
43.
Field D., Wills C. Abundant microsatellite polymorphism in Saccharomyces cerevisiae, and the different distributions of microsatellites in eight prokaryotes and S. cerevisiae, result from strong mutation pressures and a variety of selective forces. Proc. Natl. Acad. Sci. USA. 1998;95:1647–1652. [PMC free article: PMC19132] [PubMed: 9465070]
44.
Fleischmann R. D., Adams M. D., White O., Clayton R. A., Kirkness E. F., Kerlavage A. R., Bult C. J., Tomb J. F., Dougherty B. A., Merrick J. M. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science. 1995;269:496–512. [PubMed: 7542800]
45.
Forsyth M. H., Cover T. L. Intercellular communication in Helicobacter pylori: luxS is essential for the production of an extracellular signaling molecule. Infect. Immun. 2000;68:3193–3199. [PMC free article: PMC97560] [PubMed: 10816463]
46.
Foster J. W., Hall H. K. Effect of Salmonella typhimurium ferric uptake regulator (fur) mutations on iron-and pH-regulated protein synthesis. J. Bacteriol. 1992;174:4317–4323. [PMC free article: PMC206215] [PubMed: 1624426]
47.
Foynes S., Dorrell N., Ward S. J., Stabler R. A., McColm A. A., Rycroft A. N., Wren B. W. Helicobacter pylori possesses two CheY response regulators and a histidine kinase sensor, CheA, which are essential for chemotaxis and colonization of the gastric mucosa. Infect. Immun. 2000;68:2016–2023. [PMC free article: PMC97381] [PubMed: 10722597]
48.
Gorden J., Smith C. P. Acid resistance in enteric bacteria. Infect. Immun. 1993;61:364–367. [PMC free article: PMC302732] [PubMed: 8418063]
49.
Grandvalet C., Crécy-Lagard V., Mazodier P. The ClpB ATPase of Streptomyces albus G belongs to the HspR heat shock regulon. Mol. Microbiol. 1999;31:521–532. [PubMed: 10027969]
50.
Grandvalet C., Rapoport G., Mazodier P. hrcA, encoding the repressor of the groEL genes in Streptomyces albus G, is associated with a second dnaJ gene. J. Bacteriol. 1998;180:5129–5134. [PMC free article: PMC107549] [PubMed: 9748446]
51.
Greenberg J. T., Monach P. A., Chou J. H., Josephy P. D., Demple B. Positive control of a global antioxidant defense regulon activated by superoxide-generating agents in Escherichia coli. Proc. Natl. Acad. Sci. USA. 1990;87:6181–6185. [PMC free article: PMC54496] [PubMed: 1696718]
52.
Gygi D., Bailey M. J., Allison C., Hughes C. Requirement for FlhA in flagella assembly and swarm-cell differentiation by Proteus mirabilis. Mol. Microbiol. 1995;15:761–769. [PubMed: 7783646]
53.
Hall H. K., Foster J. W. The role of fur in the acid tolerance response of Salmonella typhimurium is physiologically and genetically separable from its role in iron acquisition. J. Bacteriol. 1996;178:5683–5691. [PMC free article: PMC178407] [PubMed: 8824613]
54.
Hammerschmidt S., Müller A., Sillmann H., Mühlenhoff M., Borrow R., Fox A., van Putten J., Zollinger W. D., Gerardy-Schahn R., Frosch M. Capsule phase variation in Neisseria meningitidis serogroup B by slipped-strand mispairing in the polysialyltransferase gene (siaD): correlation with bacterial invasion and the outbreak of meningococcal disease. Mol. Microbiol. 1996;20:1211–1220. [PubMed: 8809773]
55.
Handfield M., Brady L. J., Progulske-Fox A., Hillman J. D. IVIAT: a novel method to identify microbial genes expressed specifically during human infections. Trends Microbiol. 2000;8:336–339. [PubMed: 10878769]
56.
Hazell S. L., Evans D. J., Graham D. Y. Helicobacter pylori catalase. J. Gen. Microbiol. 1991;137:57–61. [PubMed: 2045782]
57.
Heithoff D. M., Sinsheimer R. L., Low D. A., Mahan M. J. An essential role for DNA adenine methylation in bacterial virulence. Science. 1999;284:967–970. [PubMed: 10320378]
58.
Henderson I. R., Owen P., Nataro J. P. Molecular switches—the on and off of bacterial phase variation. Mol. Microbiol. 1999;33:919–932. [PubMed: 10476027]
59.
Hendricks J. K., Mobley H. L. Helicobacter pylori ABC transporter: effect of allelic exchange mutagenesis on urease activity. J. Bacteriol. 1997;179:5892–5902. [PMC free article: PMC179482] [PubMed: 9294450]
60.
Hengge-Aronis R. Back to log phase: sigma S as a global regulator in the osmotic control of gene expression in Escherichia coli. Mol. Microbiol. 1996;21:887–893. [PubMed: 8885260]
61.
Hesterkamp T., Bukau B. Role of the DnaK and HscA homologs of Hsp70 chaperones in protein folding in Escherichia coli. EMBO J. 1998;17:4818–4828. [PMC free article: PMC1170811] [PubMed: 9707441]
62.
Heyde M., Portalier R. Acid shock proteins of Escherichia coli. FEMS Microbiol. Lett. 1990;57:19–26. [PubMed: 2199304]
63.
Hoffman P. S., Garduno R. A. Surface-associated heat shock proteins of Legionella pneumophila and Helicobacter pylori: roles in pathogenesis and immunity. Infect. Dis. Obstet. Gynecol. 1999;7:58–63. [PMC free article: PMC1784713] [PubMed: 10231011]
64.
Homuth G., Domm S., Kleiner D., Schumann W. Transcriptional analysis of major heat shock genes of Helicobacter pylori. J. Bacteriol. 2000;182:4257–4263. [PMC free article: PMC101936] [PubMed: 10894735]
65.
Hood D. W., Deadman M. E., Jennings M. P., Bisercic M., Fleischmann R. D., Venter J. C., Moxon E. R. DNA repeats identify novel virulence genes in Haemophilus influenzae. Proc. Natl. Acad. Sci. USA. 1996;93:11121–11125. [PMC free article: PMC38294] [PubMed: 8855319]
66.
Huesca M., Borgia S., Hoffman P., Lingwood C. A. Acidic pH changes receptor binding specificity of Helicobacter pylori: a binary adhesion model in which surface heat shock (stress) proteins mediate sulfatide recognition in gastric colonization. Infect. Immun. 1996;64:2643–2648. [PMC free article: PMC174121] [PubMed: 8698490]
67.
Huesca M., Goodwin A., Bhagwansingh A., Hoffman P., Lingwood C. A. Characterization of an acidic-pH-inducible stress protein (hsp70), a putative sulfatide binding adhesin, from Helicobacter pylori. Infect. Immun. 1998;66:4061–4067. [PMC free article: PMC108486] [PubMed: 9712748]
68.
Husson M. O., Legrand D., Spik G., Leclerc H. Iron acquisition by Helicobacter pylori: importance of human lactoferrin. Infect. Immun. 1993;61:2694–2697. [PMC free article: PMC280902] [PubMed: 8500909]
69.
Illingworth D. S., Walter K. S., Griffiths P. L., Barclay R. Siderophore production and iron-regulated envelope proteins of Helicobacter pylori. Int. J. Med. Microbiol. Virol. Parasitol. Infect. Dis. 1993;280:113–119. [PubMed: 8280932]
70.
Josenhans C., Eaton K. A., Thevenot T., Suerbaum S. Switching of flagellar motility in Helicobacter pylori by reversible length variation of a short homopolymeric sequence repeat in fliP, a gene encoding a basal body protein. Infect. Immun. 2000;68:4598–4603. [PMC free article: PMC98385] [PubMed: 10899861]
71.
Joyce E. A., Bassler B. L., Wright A. Evidence for a signaling system in Helicobacter pylori: detection of a luxS-encoded autoinducer. J. Bacteriol. 2000;182:3638–3643. [PMC free article: PMC94532] [PubMed: 10850976]
72.
Jungblut P. R., Bumann D., Haas G., Zimny-Arndt U., Holland P., Lamer S., Siejak F., Aebischer A., Meyer T. F. Comparative proteome analysis of Helicobacter pylori. Mol. Microbiol. 2000;36:710–725. [PubMed: 10844659]
72a.
Kansau I., Guillain F., Thiberge J. M., Labigne A. Nickel-binding and immunological properties of the C-terminal domain of the H. pylori GroES homolog (HspA) Mol. Microbiol. 1996;22:1013–1023. [PubMed: 8971721]
73.
Kansau I., Labigne A. Heat shock proteins of Helicobacter pylori. Aliment. Pharmacol. Ther. 1996;10(Suppl.):51–56. [PubMed: 8730259]
74.
Karita M., Tummuru M. K., Wirth H. P., Blaser M. J. Effect of growth phase and acid shock on Helicobacter pylori cagA expression. Infect. Immun. 1996;64:4501–4507. [PMC free article: PMC174404] [PubMed: 8890198]
75.
Kustu S., North A. K., Weiss D. S. Prokaryotic transcriptional enhancers and enhancer-binding proteins. Trends Biochem. Sci. 1991;16:397–402. [PubMed: 1776167]
76.
Lee I. S., Lin J., Hall H. K., Bearson B., Foster J. W. The stationary-phase sigma factor sigma S (RpoS) is required for a sustained acid tolerance response in virulent Salmonella typhimurium. Mol. Microbiol. 1995;17:155–167. [PubMed: 7476202]
77.
Lee I. S., Slonczewski J. L., Foster J. W. A low-pH-inducible, stationary-phase acid tolerance response in Salmonella typhimurium. J. Bacteriol. 1994;176:1422–1426. [PMC free article: PMC205208] [PubMed: 8113183]
78.
Leying H., Suerbaum S., Geis G., Haas R. Cloning and genetic characterization of a Helicobacter pylori flagellin gene. Mol. Microbiol. 1992;6:2863–2874. [PubMed: 1435261]
79.
Lim J. K., Gunther N. W., Zhao H., Johnson D. E., Keay S. K., Mobley H. L. In vivo phase variation of Escherichia coli type I fimbrial genes in women with urinary tract infection. Infect. Immun. 1998;66:3303–3310. [PMC free article: PMC108346] [PubMed: 9632599]
80.
Lin J., Lee I. S., Frey J., Slonczewski J. L., Foster J. W. Comparative analysis of extreme acid survival in Salmonella typhimurium, Shigella flexneri, and Escherichia coli. J. Bacteriol. 1995;177:4097–4104. [PMC free article: PMC177142] [PubMed: 7608084]
81.
Macnab, R. M. 1996. Flagella and motility, p. 123–145. In F. C. Neidhardt, R. Curtiss III, J. I., Ingraham, E. C. C. Lin, K. B. Low, B. Magasanik, W. S. Reznikoff, M. Riley, M. Schaechter, and H. E. Umbarger (ed.), Escherichia coli and Salmonella: Cellular and Molecular Biology, 2nd ed. ASM Press, Washington, D.C.
82.
Mager W. H., De Kruijff A. J. Stress-induced transcriptional activation. Microbiol. Rev. 1995;59:506–531. [PMC free article: PMC239371] [PubMed: 7565416]
83.
Manos J., Kolesnikow T., Hazell S. L. An investigation of the molecular basis of the spontaneous occurrence of a catalase-negative phenotype in Helicobacter pylori. Helicobacter. 1998;3:28–38. [PubMed: 9546115]
84.
McGee D. J., May C. A., Garner R. M., Himpsl J. M., Mobley H. L. Isolation of Helicobacter pylori genes that modulate urease activity. J. Bacteriol. 1999;181:2477–2484. [PMC free article: PMC93674] [PubMed: 10198012]
85.
McGowan C. C., Cover T. L., Blaser M. J. Helicobacter pylori and gastric acid: biological and therapeutic implications. Gastroenterology. 1996;110:926–938. [PubMed: 8608904]
86.
McGowan C. C., Necheva A., Thompson S. A., Cover T. L., Blaser M. J. Acid-induced expression of an LPS-associated gene in Helicobacter pylori. Mol. Microbiol. 1998;30:19–31. [PubMed: 9786182]
87.
Miller S., Pesci E. C., Pickett C. L. A Campylobacter jejuni homolog of the LcrD/FlbF family of proteins is necessary for flagellar biogenesis. Infect. Immun. 1993;61:2930–2936. [PMC free article: PMC280941] [PubMed: 8514397]
88.
Minamino T., Iino T., Kutsukake K. Molecular characterization of the Salmonella typhimurium flhB operon and its protein products. J. Bacteriol. 1994;176:7630–7637. [PMC free article: PMC197220] [PubMed: 8002587]
89.
Mizote T., Yoshiyama H., Nakazawa T. Urease-independent chemotactic responses of Helicobacter pylori to urea, urease inhibitors, and sodium bicarbonate. Infect. Immun. 1997;65:1519–1521. [PMC free article: PMC175162] [PubMed: 9119496]
90.
Mizuno T. Compilation of all genes encoding two-component phosphotransfer signal transducers in the genome of Escherichia coli. DNA Res. 1997;4:161–168. [PubMed: 9205844]
91.
Mobley H. L., Garner R. M., Bauerfeind P. Helicobacter pylori nickel-transport gene nixA: synthesis of catalytically active urease in Escherichia coli independent of growth conditions. Mol. Microbiol. 1995;16:97–109. [PubMed: 7651142]
92.
Murphy G. L., Connell T. D., Barritt D. S., Koomey M., Cannon J. G. Phase variation of gonococcal protein II: regulation of gene expression by slipped-strand mispairing of a repetitive DNA sequence. Cell. 1989;56:539–547. [PubMed: 2492905]
93.
Narberhaus F. Negative regulation of bacterial heat shock genes. Mol. Microbiol. 1999;31:1–8. [PubMed: 9987104]
94.
Niederhoffer E. C., Naranjo C. M., Bradley K. L., Fee J. A. Control of Escherichia coli superoxide dismutase (sodA and sodB) genes by the ferric uptake regulation (fur) locus. J. Bacteriol. 1990;172:1930–1938. [PMC free article: PMC208688] [PubMed: 2180912]
95.
Nunoshiba T. Two-stage gene regulation of the super-oxide stress response soxRS system in Escherichia coli. Crit. Rev. Eukaryot. Gene Expr. 1996;6:377–389. [PubMed: 8959373]
96.
Odenbreit S., Wieland B., Haas R. Cloning and genetic characterization of Helicobacter pylori catalase and construction of a catalase-deficient mutant strain. J. Bacteriol. 1996;178:6960–6967. [PMC free article: PMC178599] [PubMed: 8955320]
97.
Parkhill J., Wren B. W., Mungall K., Ketley J. M., Churcher C., Basham D., Chillingworth T., Davies R. M., Feltwell T., Holroyd S., Jagels K., Karlyshev A. V., Moule S., Pallen M. J., Penn C. W., Quail M. A., Rajandream M. A., Rutherford K. M., van Vliet A. H., Whitehead S., Barrell B. G. The genome sequence of the food-borne pathogen Campylobacter jejuni reveals hypervariable sequences. Nature. 2000;403:665–668. [PubMed: 10688204]
98.
Peck B., Ortkamp M., Diehl K. D., Hundt E., Knapp B. Conservation, localization and expression of HopZ, a protein involved in adhesion of Helicobacter pylori. Nucleic Acids Res. 1999;27:3325–3333. [PMC free article: PMC148566] [PubMed: 10454640]
99.
Peek R. M., Thompson S. A., Donahue J. P., Tham K. T., Atherton J. C., Blaser M. J., Miller G. G. Adherence to gastric epithelial cells induces expression of a Helicobacter pylori gene, iceA, that is associated with clinical outcome. Proc. Assoc. Am. Physicians. 1998;110:531–544. [PubMed: 9824536]
100.
Peterson S. N., Bailey C. C., Jensen J. S., Borre M. B., King E. S., Bott K. F., Hutchison III C. A. Characterization of repetitive DNA in the Mycoplasma genitalium genome: possible role in the generation of antigenic variation. Proc. Natl. Acad. Sci. USA. 1995;92:11829–11833. [PMC free article: PMC40496] [PubMed: 8524858]
101.
Ramakrishnan G., Zhao J.-L., Newton A. The cell cycle-regulated flagellar gene flbF of Caulobacter crescentus is homologous to a virulence locus of Yersinia pestis. J. Bacteriol. 1991;173:7283–7292. [PMC free article: PMC209236] [PubMed: 1938923]
102.
Romeo T. Global regulation by the small RNA-binding protein CsrA and the non-coding RNA molecule CsrB. Mol. Microbiol. 1998;29:1321–1330. [PubMed: 9781871]
103.
Russo F., Silhavy T. J. EnvZ controls the concentration of phosphorylated OmpR to mediate osmoregulation of the porin genes. J. Mol. Biol. 1991;222:567–580. [PubMed: 1660927]
104.
Sanders L. A., van Way S., Mullin D. A. Characterization of the Caulobacter crescentus flbF promoter and identification of the inferred FlbF product as a homolog of the LcrD protein from a Yersinia enterocolitica virulence plasmid. J. Bacteriol. 1992;174:857–866. [PMC free article: PMC206163] [PubMed: 1732219]
105.
Sarkari J., Pandit N., Moxon E. R., Achtman M. Variable expression of the Opc outer membrane protein in Neisseria meningitidis is caused by size variation of a promoter containing poly-cytidine. Mol. Microbiol. 1994;13:207–217. [PubMed: 7984102]
106.
Saunders N. J., Peden J. F., Hood D. W., Moxon E. R. Simple sequence repeats in the Helicobacter pylori genome. Mol. Microbiol. 1998;27:1091–1098. [PubMed: 9570395]
107.
Schmitz A., Josenhans C., Suerbaum S. Cloning and characterization of the Helicobacter pylori flbA gene, which codes for a membrane protein involved in coordinated expression of flagellar genes. J. Bacteriol. 1997;179:987–997. [PMC free article: PMC178789] [PubMed: 9023175]
108.
Schulz A., Schumann W. hrcA, the first gene of B. subtilis dnaK operon encodes a negative regulator of class I heat shock genes. J. Bacteriol. 1996;178:1088–1093. [PMC free article: PMC177769] [PubMed: 8576042]
109.
Segal E., Billyard E., So M., Storzbach S., Meyer T. F. Role of chromosomal rearrangement in N. gonorrhoeae pilus phase variation. Cell. 1985;40:293–300. [PubMed: 2857113]
110.
Silver S., Phung L. T. Bacterial heavy metal resistance: new surprises. Annu. Rev. Microbiol. 1996;50:753–789. [PubMed: 8905098]
111.
Small P., Blankenhorn D., Welty D., Zinser E., Slonczewski J. L. Acid and base resistance in Escherichia coli and Shigella flexneri: role of RpoS and growth pH. J. Bacteriol. 1994;176:1729–1737. [PMC free article: PMC205261] [PubMed: 8132468]
112.
Sperandio V., Mellies J. L., Nguyen W., Shin S., Kaper J. B. Quorum sensing controls expression of the type III secretion gene transcription and protein secretion in enterohemorrhagic and enteropathogenic Escherichia coli. Proc. Natl. Acad. Sci. USA. 1999;96:15196–15201. [PMC free article: PMC24796] [PubMed: 10611361]
113.
Spohn G., Scarlato V. Motility of Helicobacter pylori is coordinately regulated by the transcriptional activator FlgR, an NtrC homolog. J. Bacteriol. 1999;181:593–599. [PMC free article: PMC93415] [PubMed: 9882675]
114.
Spohn G., Scarlato V. The autoregulatory HspR repressor protein governs chaperone gene transcription in Helicobacter pylori. Mol. Microbiol. 1999;34:663–674. [PubMed: 10564507]
115.
Stock, J. B., and M. G. Surette. 1996. Chemotaxis, p. 1103–1129. In F. C. Neidhardt, R. Curtiss III, J. L. Ingraham, E. C. C. Lin, K. B. Low, B. Magasanik, W. S. Reznikoff, M. Riley, M. Schaechter, and H. E. Umbarger (ed.), Escherichia coli and Salmonella: Cellular and Molecular Biology, 2nd ed. ASM Press, Washington, D.C.
116.
Storz G., Imlay J. A. Oxidative stress. Curr. Opin. Microbiol. 1999;2:188–194. [PubMed: 10322176]
117.
Suerbaum S., Josenhans C., Labigne A. Cloning and genetic characterization of the Helicobacter pylori and Helicobacter mustelae flaB flagellin genes and construction of H. pylori flaA- and flaB-negative mutants by electroporation-mediated allelic exchange. J. Bacteriol. 1993;175:3278–3288. [PMC free article: PMC204724] [PubMed: 8501031]
118.
Suerbaum S., Thiberge J. M., Kansau I., Ferrero R. L., Labigne A. Helicobacter pylori hspA-hspB heat-shock gene cluster: nucleotide sequence, expression, putative function and immunogenicity. Mol. Microbiol. 1994;14:959–974. [PubMed: 7715457]
119.
Surette M. G., Miller M. B., Bassler B. L. Quorum sensing in Escherichia coli, Salmonella typhimurium, and Vibrio harveyi: a new family of genes responsible for autoinducer production. Proc. Natl. Acad. Sci. USA. 1999;96:1639–1644. [PMC free article: PMC15544] [PubMed: 9990077]
120.
Szczebara F., Dhaenens L., Armand S., Husson M. O. Regulation of the transcription of genes encoding different virulence factors in Helicobacter pylori by free iron. FEMS Microbiol. Lett. 1999;175:165–170. [PubMed: 10386365]
121.
Thies F. L., Karch H., Hartung H. P., Giegerich G. Cloning and expression of the dnaK gene of Campylobacter jejuni and antigenicity of heat shock protein 70. Infect. Immun. 1999;67:1194–1200. [PMC free article: PMC96446] [PubMed: 10024560]
122.
Thies F. L., Weishaupt A., Karch H., Hartung H. P., Giegerich G. Cloning, sequencing and molecular analysis of the Campylobacter jejuni groESL bicistronic operon. Microbiology. 1999;145(Pt 1):89–98. [PubMed: 10206714]
123.
Tomb J. F., White O., Kerlavage A. R., Clayton R. A., Sutton G. G., Fleischmann R. D., Ketchum K. A., Klenk H. P., Gill S., Dougherty B. A., Nelson K., Quackenbush J., Zhou L., Kirkness E. F., Peterson S., Loftus B., Richardson D., Dodson R., Khalak H. G., Glodek A., McKenney K., Fitzegerald L. M., Lee N., Adams M. D. et al. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature. 1997;388:539–547. [PubMed: 9252185]
124.
van Belkum A., Scherer S., van Alphen L., Verbrugh H. Short-sequence DNA repeats in prokaryotic genomes. Microbiol. Mol. Biol. Rev. 1998;62:275–293. [PMC free article: PMC98915] [PubMed: 9618442]
125.
van der Ende A., Hopman C. T., Zaat S., Essink B. B., Berkhout B., Dankert J. Variable expression of class 1 outer membrane protein in Neisseria meningitidis is caused by variation in the spacing between the −10 and −35 regions of the promoter. J. Bacteriol. 1995;177:2475–2480. [PMC free article: PMC176907] [PubMed: 7730280]
126.
Vanet A., Marsan L., Labigne A., Sagot M. F. Inferring regulatory elements from a whole genome. An analysis of Helicobacter pylori sigma(80) family of promoter signals. J. Mol. Biol. 2000;297:335–353. [PubMed: 10715205]
127.
van Putten J. P. Phase variation of lipopolysaccharide directs interconversion of invasive and immuno-resistant phenotypes of Neisseria gonorrhoeae. EMBO J. 1993;12:4043–4051. [PMC free article: PMC413697] [PubMed: 7693451]
128.
van Vliet A. H. M., Baillon M. L. A., Penn C. W., Ketley J. M. Campylobacter jejuni contains two Fur homologs: characterisation of iron-responsive regulation of peroxide stress defence genes by the PerR repressor. J. Bacteriol. 1999;181:6371–6376. [PMC free article: PMC103772] [PubMed: 10515927]
129.
van Vliet A. H. M., de Vries N., Bereswill S., Kist M., Kuipers E. J., Vandenbroucke-Grauls C. M. J. E., Kusters J. G. The role of the ferric uptake regulator (Fur) protein in Helicobacter pylori iron uptake. Gut. 1999;45(S3):A27.
130.
van Vliet A. H. M., Bereswill S., Waidner B., Kuipers E. J., Vandenbroucke-Grauls C. M. J. E., Kusters J. G. Fur-mediated nickel-responsive regulation of urease expression in Helicobacter pylori. Gut. 2000;47(S1):A17–A18.
131.
van Vliet A. H. M., Wooldridge K. G., Ketley J. M. Iron-responsive gene regulation in a Campylobacter jejuni fur mutant. J. Bacteriol. 1998;180:5291–5298. [PMC free article: PMC107575] [PubMed: 9765558]
132.
Walker, G. C. 1996. The SOS response of Escherichia coli, p. 1400–1416. In F. C. Neidhardt, R. Curtiss III, J. L. Ingraham, E. C. C. Lin, K. B. Low, B. Magasanik, W. S. Reznikoff, M. Riley, M. Schaechter, and H. E. Umbarger (ed.), Escherichia coli and Salmonella typhimurium: Cellular and Molecular Biology, 1st ed. ASM Press, Washington, D.C.
133.
Walkup L. K. B., Kogoma T. Escherichia coli proteins inducible by oxidative stress mediated by the superoxide radical. J. Bacteriol. 1989;171:1479–1484. [PMC free article: PMC209769] [PubMed: 2537820]
134.
Wang G., Rasko D. A., Sherburne R., Taylor D. E. Molecular genetic basis for the variable expression of Lewis Y antigen in Helicobacter pylori: analysis of the alpha (1,2) fucosyltransferase gene. Mol. Microbiol. 1999;31:1265–1274. [PubMed: 10096092]
135.
Wei B., Shin S., LaPorte D., Wolfe A. J., Romeo T. Global regulatory mutations in csrA and rpoS cause severe central carbon stress in Escherichia coli in the presence of acetate. J. Bacteriol. 2000;182:1632–1640. [PMC free article: PMC94461] [PubMed: 10692369]
136.
Whitely M., Lee K. M., Greenberg E. P. Identification of genes controlled by quorum sensing in Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. USA. 1999;96:13904–13909. [PMC free article: PMC24163] [PubMed: 10570171]
137.
Wooldridge K. G., Williams P. H. Iron uptake mechanisms of pathogenic bacteria. FEMS Microbiol. Rev. 1993;12:325–348. [PubMed: 8268005]
138.
Worst D. J., Otto B. R., de Graaff J. Iron-repressible outer membrane proteins of Helicobacter pylori involved in heme uptake. Infect. Immun. 1995;63:4161–4165. [PMC free article: PMC173585] [PubMed: 7558334]
139.
Wu J., Newton A. Regulation of the Caulobacter flagellar gene hierarchy: not just for motility. Mol. Microbiol. 1997;24:233–239. [PubMed: 9159510]
140.
Yamaguchi H., Osaki T., Kurihara N., Taguchi H., Hanawa T., Yamamoto T., Kamiya S. Heat-shock protein 60 homologue of Helicobacter pylori is associated with adhesion of H. pylori to human gastric epithelial cells. J. Med. Microbiol. 1997;46:825–831. [PubMed: 9364138]
141.
Yamaguchi H., Osaki T., Taguchi H., Hanawa T., Yamamoto T., Kamiya S. Induction and epitope analysis of Helicobacter pylori heat shock protein. J. Gastroenterol. 1996;31(Suppl. 9):12–15. [PubMed: 8959511]
142.
Yamaoka Y., Kwon D. H., Graham D. Y. A Mr 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori. Proc. Natl. Acad. Sci. USA. 2000;97:7533–7538. [PMC free article: PMC16580] [PubMed: 10852959]
143.
Yokota K., Hirai Y., Haque M., Hayashi S., Isogai H., Sugiyama T., Nagamachi E., Tsukada Y., Fujii N., Oguma K. Heat shock protein produced by Helicobacter pylori. Microbiol. Immunol. 1994;38:403–405. [PubMed: 7935068]
144.
Zheng M., Doan B., Schneider T. D., Storz G. OxyR and SoxRS regulation of fur. J. Bacteriol. 1999;181:4639–4643. [PMC free article: PMC103597] [PubMed: 10419964]
Copyright © 2001, ASM Press.
Bookshelf ID: NBK2431PMID: 21290732

Views

  • PubReader
  • Print View
  • Cite this Page

Related information

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...