Detailed
            <i>In Vivo</i>
            Analysis of the Role of
            <i>Helicobacter pylori</i>
            Fur in Colonization and Disease

Miles, Shana; Piazuelo, M. Blanca; Semino–Mora, Cristina; Washington, Mary Kay; Dubois, A.; Peek, Richard M.; Correa, Pelayo; Merrell, D. Scott

doi:10.1128/iai.00190-10

Cited by 29 publications

(43 citation statements)

References 65 publications

(87 reference statements)

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“…Also, like the Che Ϫ mutant defect, the fur defect is less significant in the corpus. Fur regulates some chemotaxis genes, such as cheV1, possibly explaining the overlapping phenotypes (13,33). Thus, these three bacterial properties affect corpus-antrum localization in different ways and suggest that normal H. pylori variations might influence stomach region density.…”

Section: Discussionmentioning

confidence: 99%

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Helicobacter pylori Requires TlpD-Driven Chemotaxis To Proliferate in the Antrum

et al. 2012

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ABSTRACTDifferent disease outcomes ofHelicobacter pyloriinfection correlate with distinct inflammation patterns. These different inflammatory distributions may be initiated by differences in bacterial localization. OneH. pyloriproperty known to affect murine stomach localization is chemotaxis, the ability to move in response to chemical cues. In this report, we used nonchemotactic mutants (Che−) to analyze whether chemotaxis is required for initial colonization of particular stomach regions or for subsequent growth therein. We found thatH. pyloribehaves differently in the corpus, antrum, and corpus-antrum transition zone subregions of the stomach. This outcome suggests that these regions contain unique chemotactic signals. In the corpus,H. pyloriutilizes chemotaxis for initial localization but not for subsequent growth. In contrast, in the antrum and the corpus-antrum transition zone, chemotaxis does not help initial colonization but does promote subsequent proliferation. To determine which chemoreceptor is responsible for the corpus-antrum phenotypes, we infected mice with strains lacking each chemoreceptor. Strains lacking TlpA, TlpB, or TlpC displayed only modest deviations from the wild-type phenotype, while strains lacking TlpD resembled the Che−mutant in their antral colonization defect and fared even worse than the Che−mutant in the corpus. Additional analysis showed that inflammation is worse in the antrum than in the corpus in both wild-type and Che−mutant infections. These results suggest that chemotaxis, specifically, that controlled by TlpD, is necessary forH. pylorito survive or grow in the environment of increased inflammation in the antrum.

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Section: Discussionmentioning

confidence: 99%

“…Studies have shown that different H. pylori strains achieve higher bacterial colonization numbers in either the corpus or the antrum (1,27,33). For example, strain X47 has a strong preference for the corpus, and strain SS1 has an antral preference or colonizes the antrum and corpus equally, depending on the study (1,27,47).…”

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confidence: 99%

Helicobacter pylori Requires TlpD-Driven Chemotaxis To Proliferate in the Antrum

et al. 2012

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“…The vast majority of these studies have focused on resistance to various stressful environments (10,18,27,60), identification of the regulon of genes controlled by each regulatory factor (16, 17, 19-21, 23, 61), or elucidation of the contribution of each regulator to colonization in an animal model (8)(9)(10)(11). Despite the evidence supporting the fact that the Fur, NikR, and ArsRS regulons show considerable overlap, very few studies (8,17,25,53) have attempted to analyze the combined effect of these regulatory factors in H. pylori biology.…”

Section: Discussionmentioning

confidence: 99%

“…Three key nodes within this regulatory structure are represented by the following regulatory proteins: Fur, the ferric uptake regulator; NikR, a nickel response regulator; and ArsRS, an acid-responsive two-component system (7). The prominent roles of these regulators are highlighted by the fact that all three are required for wild-type colonization levels in animal models (8)(9)(10)(11). The importance of the OmpR-like response regulator ArsR is further demonstrated by the fact that it is essential for in vitro survival.…”

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confidence: 99%

Characterization of Key Helicobacter pylori Regulators Identifies a Role for ArsRS in Biofilm Formation

et al. 2016

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Helicobacter pylori must be able to rapidly respond to fluctuating conditions within the stomach. Despite this need for constant adaptation, H. pylori encodes few regulatory proteins. Of the identified regulators, the ferric uptake regulator (Fur), the nickel response regulator (NikR), and the two-component acid response system (ArsRS) are each paramount to the success of this pathogen. While numerous studies have individually examined these regulatory proteins, little is known about their combined effect. Therefore, we constructed a series of isogenic mutant strains that contained all possible single, double, and triple regulatory mutations in Fur, NikR, and ArsS. A growth curve analysis revealed minor variation in growth kinetics across the strains; these were most pronounced in the triple mutant and in strains lacking ArsS. Visual analysis showed that strains lacking ArsS formed large aggregates and a biofilm-like matrix at the air-liquid interface. Biofilm quantification using crystal violet assays and visualization via scanning electron microscopy (SEM) showed that all strains lacking ArsS or containing a nonphosphorylatable form of ArsR (ArsR-D52N mutant) formed significantly more biofilm than the wild-type strain. Molecular characterization of biofilm formation showed that strains containing mutations in the ArsRS pathway displayed increased levels of cell aggregation and adherence, both of which are key to biofilm development. Furthermore, SEM analysis revealed prevalent coccoid cells and extracellular matrix formation in the ArsR-D52N, ⌬nikR ⌬arsS, and ⌬fur ⌬nikR ⌬arsS mutant strains, suggesting that these strains may have an exacerbated stress response that further contributes to biofilm formation. Thus, H. pylori ArsRS has a previously unrecognized role in biofilm formation. IMPORTANCEDespite a paucity of regulatory proteins, adaptation is key to the survival of H. pylori within the stomach. While prior studies have focused on individual regulatory proteins, such as Fur, NikR, and ArsRS, few studies have examined the combined effect of these factors. Analysis of isogenic mutant strains that contained all possible single, double, and triple regulatory mutations in Fur, NikR, and ArsS revealed a previously unrecognized role for the acid-responsive two-component system ArsRS in biofilm formation.

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“…Although substitution mutations at the Fur R88 position are not found commonly in H. pylori isolates from humans, an R88H mutation identical to the mutation observed in the present study has been detected in at least three H. pylori isolates from humans (57). Previous studies have shown that H. pylori Fur has a role in resistance to high-salt conditions (49) and resistance to oxidative stress (50-54) and contributes to H. pylori colonization of the stomach (58). To further investigate the functional consequences of the Fur-R88H mutation, we compared the abilities of H. pylori strains producing either WT Fur or Fur-R88H to grow in medium containing elevated salt concentrations or in oxidative-stress environments.…”

Section: Figmentioning

confidence: 50%

Helicobacter pylori Adaptation In Vivo in Response to a High-Salt Diet

et al. 2015

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e Helicobacter pylori exhibits a high level of intraspecies genetic diversity. In this study, we investigated whether the diversification of H. pylori is influenced by the composition of the diet. Specifically, we investigated the effect of a high-salt diet (a known risk factor for gastric adenocarcinoma) on H. pylori diversification within a host. We analyzed H. pylori strains isolated from Mongolian gerbils fed either a high-salt diet or a regular diet for 4 months by proteomic and whole-genome sequencing methods. Compared to the input strain and output strains from animals fed a regular diet, the output strains from animals fed a highsalt diet produced higher levels of proteins involved in iron acquisition and oxidative-stress resistance. Several of these changes were attributable to a nonsynonymous mutation in fur (fur-R88H). Further experiments indicated that this mutation conferred increased resistance to high-salt conditions and oxidative stress. We propose a model in which a high-salt diet leads to high levels of gastric inflammation and associated oxidative stress in H. pylori-infected animals and that these conditions, along with the high intraluminal concentrations of sodium chloride, lead to selection of H. pylori strains that are most fit for growth in this environment. Helicobacter pylori is a Gram-negative bacterium that persistently colonizes the human stomach in half of the world's population (1, 2). H. pylori exhibits a high level of intraspecies genetic diversity, characterized by marked variation among strains in gene content, as well as a high level of variation in the nucleotide sequences of individual genes (3, 4). A high rate of allelic diversity is attributable to both a high mutation rate and intraspecies recombination (5, 6).Most H. pylori-infected persons remain asymptomatic, but the presence of this bacterium increases the risk of peptic ulcer disease and gastric cancer (1, 2, 7, 8). The clinical outcome of H. pylori infection is determined by a combination of bacterial, host, and environmental factors. For example, H. pylori strains containing the cag pathogenicity island (PAI) are associated with a higher risk of symptomatic disease than are strains that lack the cag PAI (9). One of the proteins encoded by the cag PAI, CagA, enters host cells and causes numerous cellular alterations linked to malignant transformation (10). The cag PAI also encodes multiple protein components of a type IV secretion system required for entry of CagA into host cells (11). H. pylori strains that secrete specific types of the VacA toxin are also linked to adverse disease outcome, in comparison to strains that secrete relatively nontoxic forms of the VacA protein (12, 13).One of the environmental factors associated with increased gastric cancer risk is a high-salt diet (14). Epidemiologic studies have demonstrated a link between high dietary salt consumption and increased gastric cancer risk in many parts of the world (15-17), and a high-salt diet also increases the gastric cancer risk in animal models (...

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Detailed In Vivo Analysis of the Role of Helicobacter pylori Fur in Colonization and Disease

Cited by 29 publications

References 65 publications

Helicobacter pylori Requires TlpD-Driven Chemotaxis To Proliferate in the Antrum

Helicobacter pylori Requires TlpD-Driven Chemotaxis To Proliferate in the Antrum

Characterization of Key Helicobacter pylori Regulators Identifies a Role for ArsRS in Biofilm Formation

Helicobacter pylori Adaptation In Vivo in Response to a High-Salt Diet

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