Identification and Characterization of Novel Helicobacter pylori apo-Fur-Regulated Target Genes

Carpenter, Beth M.; Gilbreath, Jeremy J.; Pich, Óscar Q.; McKelvey, Ann M.; Maynard, Ernest L.; Li, Zhao Zhang; Merrell, D. Scott

doi:10.1128/jb.01026-13

Cited by 36 publications

(43 citation statements)

References 53 publications

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“…For instance, the H. pylori Fur protein was not only found to be involved in iron homeostasis, but it also participated in several other additional pathways including those of oxidative stress resistance (Harris et al, 2002) and acid regulation (Bijlsma et al, 2002; van Vliet et al, 2004), and has been found essential for colonization of the gastric mucosa (Bury-Mone et al, 2004). Moreover, unlike Fur homologs in other species, H. pylori Fur has been found to mediate gene regulation even in its iron-free (apo) form (Bereswill et al, 2000; Delany et al, 2001; Carpenter et al, 2013). Interestingly, whereas most conditions tested here showed only moderate effects on Fur expression, biofilm formation resulted in a marked up regulation of the gene, suggesting functions beyond regulation of iron metabolism.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Transcription Factors of Helicobacter pylori under Different Environmental Conditions

et al. 2017

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Helicobacter pylori is a Gram-negative bacterium that colonizes the human gastric mucosa and causes peptic ulcers and gastric carcinoma. H. pylori strain 26695 has a small genome (1.67 Mb), which codes for few known transcriptional regulators that control bacterial metabolism and virulence. We analyzed by qRT-PCR the expression of 16 transcriptional regulators in H. pylori 26695, including the three sigma factors under different environmental conditions. When bacteria were exposed to acidic pH, urea, nickel, or iron, the sigma factors were differentially expressed with a particularly strong induction of fliA. The regulatory genes hrcA, hup, and crdR were highly induced in the presence of urea, nickel, and iron. In terms of biofilm formation fliA, flgR, hp1021, fur, nikR, and crdR were induced in sessile bacteria. Transcriptional expression levels of rpoD, flgR, hspR, hp1043, and cheY were increased in contact with AGS epithelial cells. Kanamycin, chloramphenicol, and tetracycline increased or decreased expression of regulatory genes, showing that these antibiotics affect the transcription of H. pylori. Our data indicate that environmental cues which may be present in the human stomach modulate H. pylori transcription.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Transcription Factors of Helicobacter pylori under Different Environmental Conditions

et al. 2017

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“…Furthermore, H. pylori utilizes the Fur master regulator, which senses iron and other metals, as a global transcriptional regulator important for multiple stresses and virulence (Bijlsma et al ., ; Bury‐Mone et al ., ). Interestingly, H. pylori Fur is able to act as an activator and as a repressor, in its iron‐bound form as well as in its apo form (Delany et al ., ; Pich et al ., ; Carpenter et al ., ). In addition to many conserved iron‐dependent cellular processes, H. pylori fur has been found to regulate virulence by upregulation of the expression of the two main virulence factors, VacA and CagA (Raghwan and Chowdhury, ).…”

Section: H Pylori Transcriptional Regulators Respond To Acid and Metalsmentioning

confidence: 97%

How Helicobacter pylori senses, targets and interacts with the gastric epithelium

Keilberg

Ottemann

2016

Environmental Microbiology

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SummaryHelicobacter pylori is a human-specific pathogen that chronically infects about 50% of the world's population. After travelling through the harsh environment of the stomach lumen, H. pylori colonizes the mucosal surface and within the glands of the human stomach. During colonization, H. pylori uses motility and its chemotaxis signalling system to sense the environment to reach the gastric epithelium for colonization, where it is able to attach to the epithelial surface. The H. pylori population inside the stomach contains a subgroup of bacteria that are attached to the gastric epithelium and a larger subgroup of nonattached bacteria that are freely swimming. To establish a tight interaction between H. pylori and epithelial cells, the bacterium produces a variety of adhesins and delivers virulence factors. These lead to alterations in the host signalling pathways, inducing proinflammatory responses, apoptosis, uncontrolled cell proliferation, and eventually peptic ulcers and gastric cancer. To prevent disease and find a vaccine or better treatments, it is crucial to understand how H. pylori is able to sense its niche for chronic infection inside the stomach and how its virulence factors interact with the epithelial target cells.

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“…In the absence of iron, Fur exists as an inactive monomer; however, increasing ferrous iron levels leads to dimerization and Fur binding to the promoter regions of target genes, subsequently blocking RNA polymerase binding and leading to decreased transcription (21). In Helicobacter pylori Fur has also been shown to bind DNA in the absence of iron in what is termed apo-Fur-mediated regulation (22), though this has not yet been definitely shown in N. gonorrhoeae. One of the best examples of iron-mediated direct repression by Fur involves transcriptional control of gonococcal genes that encode proteins acting to scavenge free iron from the host, including the transferrin binding proteins (TbpAB) and the ferric binding protein (FbpABC) (23).…”

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Characterization of the Neisseria gonorrhoeae Iron and Fur Regulatory Network

McClure

Nudel

et al. 2016

J Bacteriol

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The Neisseria gonorrhoeae ferric uptake regulator (Fur) protein controls expression of iron homeostasis genes in response to intracellular iron levels. In this study, using transcriptome sequencing (RNA-seq) analysis of an N. gonorrhoeae fur strain, we defined the gonococcal Fur and iron regulons and characterized Fur-controlled expression of an ArsR-like DNA binding protein.We observed that 158 genes (8% of the genome) showed differential expression in response to iron in an N. gonorrhoeae wildtype or fur strain, while 54 genes exhibited differential expression in response to Fur. The Fur regulon was extended to additional regulators, including NrrF and 13 other small RNAs (sRNAs), and two transcriptional factors. One transcriptional factor, coding for an ArsR-like regulator (ArsR), exhibited increased expression under iron-replete conditions in the wild-type strain but showed decreased expression across iron conditions in the fur strain, an effect that was reversed in a fur-complemented strain. Fur was shown to bind to the promoter region of the arsR gene downstream of a predicted 70 promoter region. Electrophoretic mobility shift assay (EMSA) analysis confirmed binding of the ArsR protein to the norB promoter region, and sequence analysis identified two additional putative targets, NGO1411 and NGO1646. A gonococcal arsR strain demonstrated decreased survival in human endocervical epithelial cells compared to that of the wild-type and arsR-complemented strains, suggesting that the ArsR regulon includes genes required for survival in host cells. Collectively, these results demonstrate that the N. gonorrhoeae Fur functions as a global regulatory protein to repress or activate expression of a large repertoire of genes, including additional transcriptional regulatory proteins. IMPORTANCEGene regulation in bacteria in response to environmental stimuli, including iron, is of paramount importance to both bacterial replication and, in the case of pathogenic bacteria, successful infection. Bacterial DNA binding proteins are a common mechanism utilized by pathogens to control gene expression under various environmental conditions. Here, we show that the DNA binding protein Fur, expressed by the human pathogen Neisseria gonorrhoeae, controls the expression of a large repertoire of genes and extends this regulon by controlling expression of additional DNA binding proteins. One of these proteins, an ArsRlike regulator, was required for N. gonorrhoeae survival within host cells. These results show that the Fur regulon extends to additional regulatory proteins, which together contribute to gonococcal mechanisms of pathogenesis.

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Identification and Characterization of Novel Helicobacter pylori apo-Fur-Regulated Target Genes

Cited by 36 publications

References 53 publications

Gene Expression Profiling of Transcription Factors of Helicobacter pylori under Different Environmental Conditions

Gene Expression Profiling of Transcription Factors of Helicobacter pylori under Different Environmental Conditions

How Helicobacter pylori senses, targets and interacts with the gastric epithelium

Characterization of the Neisseria gonorrhoeae Iron and Fur Regulatory Network

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