NapA protects Helicobacter pylori from oxidative stress damage, and its production is influenced by the ferric uptake regulator

Cooksley, Clare; Jenks, Peter J.; Green, Andrew; Cockayne, Alan; Logan, R. P. H.; Hardie, Kim R.

doi:10.1099/jmm.0.05070-0

Cited by 102 publications

(110 citation statements)

References 37 publications

(71 reference statements)

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“…Nevertheless, the stationary-phase survival and morphology defects exhibited by ⌬spoT (ppGpp 0 ) mutants (138) point to the importance of maintaining ppGpp levels during entry into stationary phase. At this transition, H. pylori also induces the expression of virulence factors such as flagellin and napA, encoding a homologue of Dps (DNA protection during starvation) that is thought to protect against oxidative stress damage (48). Therefore, the stringent response pathway likely coordinates virulence factor expression with growth phase.…”

Section: Helicobacter Pylorimentioning

confidence: 99%

ppGpp Conjures Bacterial Virulence

Dalebroux

Svensson

Gaynor

et al. 2010

Microbiol Mol Biol Rev

333

364

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SUMMARY Like for all microbes, the goal of every pathogen is to survive and replicate. However, to overcome the formidable defenses of their hosts, pathogens are also endowed with traits commonly associated with virulence, such as surface attachment, cell or tissue invasion, and transmission. Numerous pathogens couple their specific virulence pathways with more general adaptations, like stress resistance, by integrating dedicated regulators with global signaling networks. In particular, many of nature's most dreaded bacteria rely on nucleotide alarmones to cue metabolic disturbances and coordinate survival and virulence programs. Here we discuss how components of the stringent response contribute to the virulence of a wide variety of pathogenic bacteria.

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Section: Helicobacter Pylorimentioning

confidence: 99%

ppGpp Conjures Bacterial Virulence

Dalebroux

Svensson

Gaynor

et al. 2010

Microbiol Mol Biol Rev

333

364

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“…There was little or no inhibition of P nifS -Fur interaction by P napA . Cooksley et al (4) showed that napA in H. pylori is repressed by Fur but that expression is induced when the cells are grown in medium supplemented with FeCl 3 , and in a fur mutant strain napA expression did not depend on iron levels (4). In our study, the competition experiment was performed in the presence of MnCl 2 (a preferable substitute for iron, as previously described; see reference 11), which is needed for Fur-P nifS binding.…”

Section: Figmentioning

confidence: 99%

Regulation of theHelicobacter pyloriFe-S Cluster Synthesis Protein NifS by Iron, Oxidative Stress Conditions, and Fur

et al. 2006

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Transcription of both chromosomal and extrachromosomally introduced nifS was regulated (up-expressed) by oxygen or by supplemental iron conditions. This up-expression was not observed in a fur mutant strain background or when an iron chelator was added. Iron-bound Fur (but not apo-Fur) recognized the nifS promoter, and Fur bound significantly farther upstream (؊155 bp to ؊190 bp and ؊210 to ؊240 bp) in the promoter than documented Helicobacter pylori Fur binding regions. This binding was stronger than Fur recognition of the flgE or napA promoter and includes a Fur recognition sequence common to the H. pylori pfr and sodB upstream areas. Studies of Fur-regulated genes in H. pylori have indicated that apo-Fur acts as a repressor, but our results demonstrate that iron-bound Fur activates (nifS) transcription.The human gastric pathogen Helicobacter pylori is well adapted for colonizing a unique niche, the stomach mucosa (3). In the mucosa it is subject to severe oxidative stress from the oxidative burst of the host immune system, which results in production of a variety of reactive oxygen intermediates (ROI) that damage macromolecules of the bacterium (21). Due to the Fenton reaction, the ROI are especially a problem in the presence of excess free intracellular iron (7). Considering the persistent nature of H. pylori, it is not surprising that the pathogen has a repertoire of enzymes involved in detoxification of the oxidative agents or in repairing the oxidized macromolecules in the cell (1,17,18,22,24).Although combating oxidative stress is a key to H. pylori survival, we know little about regulation of expression of the specific genes involved. To aid in understanding the overall oxygen stress-modulated gene expression in H. pylori, we compared the global gene expression of H. pylori grown at 2% versus 12% oxygen by using a microarray approach. Preliminary results from these studies showed an up-expression of expected genes, such as thioredoxin reductase, thioredoxin, superoxide dismutase (SOD), and thiol peroxidase, all enzymes known to be directly involved in combating oxidative stress. In addition, among the other highly up-regulated genes was one encoding the Fe-S cluster synthesis protein NifS. We observed an approximately fivefold up-regulation of the nifSnifU operon (hp0220 and hp0221) after a 2-h shift from 2% to 12% O 2 (Abstr. 105th Gen. Meet. Am. Soc. Microbiol., abstr. K-063, 2005). NifS belongs to the crucial IscS family of proteins, which is involved in Fe-S cluster formation (12). The NifS proteins provide sulfur donation via an L-cysteine desulfurase activity. The cluster maturation proteins are usually considered to be essential "housekeeping" proteins, as nearly all organisms have multiple proteins that require Fe-S clusters for their function. Thus, inactivation of the H. pylori nifS-nifU operon (hp0220 and hp0221) was previously shown to be lethal to the bacterium (12, 13).In this study we performed promoter-reporter gene fusions to determine the regulation of the nifS-nifU operon under condit...

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“…However, investigations in human patients found no correlation between neutrophil activation and H. pylori NapA expression, suggesting that this function may not be important clinically (64). Subsequently, the NapA protein was implicated in oxidative stress responses, as NapA-deficient H. pylori are more susceptible to oxidative damage in vitro (27). Deficiency of a range of antioxidant enzymes, including Hp-SOD, KatA, Hp-Tpx, and AhpC, results in a compensatory increase in NapA production (76), suggesting that it may function as a secondary antioxidant that becomes important when other defenses are overwhelmed.…”

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confidence: 99%