scholarly journals Detoxification of 7-Dehydrocholesterol Fatal to Helicobacter pylori Is a Novel Role of Cholesterol Glucosylation

2012 ◽  
Vol 195 (2) ◽  
pp. 359-367 ◽  
Author(s):  
Hirofumi Shimomura ◽  
Kouichi Hosoda ◽  
David J. McGee ◽  
Shunji Hayashi ◽  
Kenji Yokota ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Cell Membrane ◽  
Membrane Lipid ◽  
Host Immune System ◽  
Content Type ◽  
Mucosal Tissues ◽  
Gene Mutant ◽  
A Cell ◽  
H Pylori

ABSTRACTThe glucosylation of free cholesterol (FC) byHelicobacter pyloricells has various biological significances for the survival of this bacterium.H. pyloricells with glucosylated FC are capable of evading host immune systems, such as phagocytosis by macrophages and activation of antigen-specific T cells, and surviving in the gastric mucosal tissues for long periods. An additional role of cholesterol glucosylation in the survival ofH. pyloriwhich is distinct from the role of escaping the host immune system, however, has yet to be identified. This study demonstrated that 7-dehydrocholesterol (7dFC), an FC precursor, is a toxic compound fatal toH. pyloricells, but the cell membrane ofH. pyloriis capable of absorbing this toxic sterol via glucosylation. In contrast to the case with 7dFC, no toxicity toH. pyloricells was detected from the glucosylated 7dFC. In addition,cgtgene mutantH. pyloricells that cannot glucosylate cholesterols had higher susceptibility to the toxic action of 7dFC than wild-typeH. pyloricells. These results indicate that thecgtgene product ofH. pyloriserves to detoxify the sterol fatal to this bacterium and to permit this toxic sterol as a cell membrane lipid component. In summary, this study defined a novel role of cholesterol glucosylation inH. pylori.

scholarly journals Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Adria Carbo ◽  
Danyvid Olivares-Villagómez ◽  
Raquel Hontecillas ◽  
Josep Bassaganya-Riera ◽  
Rupesh Chaturvedi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Wild Type ◽  
Content Type ◽  
Interleukin 21 ◽  
H Pylori ◽  
Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

scholarly journals Dietary Composition Influences Incidence of Helicobacter pylori-Induced Iron Deficiency Anemia and Gastric Ulceration

2016 ◽  
Vol 84 (12) ◽  
pp. 3338-3349 ◽  
Author(s):  
Amber C. Beckett ◽  
M. Blanca Piazuelo ◽  
Jennifer M. Noto ◽  
Richard M. Peek ◽  
M. Kay Washington ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Gastric Ulceration ◽  
High Salt ◽  
Gastric Ulcers ◽  
Deficiency Anemia ◽  
Content Type ◽  
H Pylori

Epidemiologic studies have provided conflicting data regarding an association betweenHelicobacter pyloriinfection and iron deficiency anemia (IDA) in humans. Here, a Mongolian gerbil model was used to investigate a potential role ofH. pyloriinfection, as well as a possible role of diet, inH. pylori-associated IDA. Mongolian gerbils (eitherH. pyloriinfected or uninfected) received a normal diet or one of three diets associated with increasedH. pylorivirulence: high-salt, low-iron, or a combination of a high-salt and low-iron diet. In an analysis of all infected animals compared to uninfected animals (independent of diet),H. pylori-infected gerbils had significantly lower hemoglobin values than their uninfected counterparts at 16 weeks postinfection (P< 0.0001). The mean corpuscular volume (MCV) and serum ferritin values were significantly lower inH. pylori-infected gerbils than in uninfected gerbils, consistent with IDA. Leukocytosis and thrombocytosis were also detected in infected gerbils, indicating the presence of a systemic inflammatory response. In comparison to uninfected gerbils,H. pylori-infected gerbils had a higher gastric pH, a higher incidence of gastric ulcers, and a higher incidence of fecal occult blood loss. Anemia was associated with the presence of gastric ulceration but not gastric cancer. Infected gerbils consuming diets with a high salt content developed gastric ulcers significantly more frequently than gerbils consuming a normal-salt diet, and the lowest hemoglobin levels were in infected gerbils consuming a high-salt/low-iron diet. These data indicate thatH. pyloriinfection can cause IDA and that the composition of the diet influences the incidence and severity ofH. pylori-induced IDA.

scholarly journals Noncatalytic Antioxidant Role forHelicobacter pyloriUrease

2018 ◽  
Vol 200 (17) ◽  
Author(s):  
Alan A. Schmalstig ◽  
Stéphane L. Benoit ◽  
Sandeep K. Misra ◽  
Joshua S. Sharp ◽  
Robert J. Maier
Keyword(s):  
Helicobacter Pylori ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Repair System ◽  
Content Type ◽  
Urease Enzyme ◽  
Catalytic Role ◽  
Methionine Residues ◽  
H Pylori

ABSTRACTThe well-studied catalytic role of urease, the Ni-dependent conversion of urea into carbon dioxide and ammonia, has been shown to protectHelicobacter pyloriagainst the low pH environment of the stomach lumen. We hypothesized that the abundantly expressed urease protein can play another noncatalytic role in combating oxidative stress via Met residue-mediated quenching of harmful oxidants. Three catalytically inactive urease mutant strains were constructed by single substitutions of Ni binding residues. The mutant versions synthesize normal levels of urease, and the altered versions retained all methionine residues. The three site-directed urease mutants were able to better withstand a hypochlorous acid (HOCl) challenge than a ΔureABdeletion strain. The capacity of purified urease to protect whole cells via oxidant quenching was assessed by adding urease enzyme to nongrowing HOCl-exposed cells. No wild-type cells were recovered with oxidant alone, whereas urease addition significantly aided viability. These results suggest that urease can protectH. pyloriagainst oxidative damage and that the protective ability is distinct from the well-characterized catalytic role. To determine the capability of methionine sulfoxide reductase (Msr) to reduce oxidized Met residues in urease, purifiedH. pyloriurease was exposed to HOCl and a previously described Msr peptide repair mixture was added. Of the 25 methionine residues in urease, 11 were subject to both oxidation and to Msr-mediated repair, as identified by mass spectrometry (MS) analysis; therefore, the oxidant-quenchable Met pool comprising urease can be recycled by the Msr repair system. Noncatalytic urease appears to play an important role in oxidant protection.IMPORTANCEChronicHelicobacter pyloriinfection can lead to gastric ulcers and gastric cancers. The enzyme urease contributes to the survival of the bacterium in the harsh environment of the stomach by increasing the local pH. In addition to combating acid,H. pylorimust survive host-produced reactive oxygen species to persist in the gastric mucosa. We describe a cyclic amino acid-based antioxidant role of urease, whereby oxidized methionine residues can be recycled by methionine sulfoxide reductase to again quench oxidants. This work expands our understanding of the role of an already acknowledged pathogen virulence factor and specifically expands our knowledge ofH. pylorisurvival mechanisms.

scholarly journals Role of apoptosis induced by Helicobacter pylori infection in the development of duodenal ulcer

Gut ◽  
1999 ◽  
Vol 44 (4) ◽  
pp. 456-462 ◽  
Author(s):  
K Kohda ◽  
K Tanaka ◽  
Y Aiba ◽  
M Yasuda ◽  
T Miwa ◽  
...  
Keyword(s):  
Duodenal Ulcer ◽  
Helicobacter Pylori ◽  
Clinical Stage ◽  
Endoscopic Examination ◽  
Gastric Epithelium ◽  
Antral Mucosa ◽  
Biopsy Specimens ◽  
A Cell ◽  
H Pylori

BACKGROUNDHelicobacter pylori affects gastric epithelium integrity by acceleration of apoptosis. However, it remains unclear what product of the bacteria causes apoptosis, or whether or not the apoptosis is involved in the development of ulcers.AIMSTo elucidate the factor from H pylori that causes acceleration of apoptosis and the role of apoptosis in the development of duodenal ulcer in H pylori infection.PATIENTSFiveH pylori negative healthy volunteers, 47H pylori positive patients with duodenal ulcer, and 35 H pylori positive patients with gastric ulcer.METHODSAn endoscopic examination was carried out to diagnose ulcers and determine their clinical stage. To analyse apoptosis, a cell cycle analysis was performed using biopsy specimens.RESULTSThere was a significant correlation between the urease activity of theH pylori strain and the level of apoptosis induced by this bacterial strain. Moreover, in duodenal ulcer patients infected with H pylori, the patients with an active ulcer exhibited a significantly higher level of apoptosis than those with ulcers at both the healing and scarring stages.CONCLUSIONThese findings suggest that acceleration of apoptosis in the antral mucosa caused by the urease of H pylori plays a crucial role in the development of ulcers in the duodenum.

scholarly journals The Bifunctional Enzyme SpoT Is Involved in the Clarithromycin Tolerance of Helicobacter pylori by Upregulating the Transporters HP0939, HP1017, HP0497, and HP0471

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Xiwen Geng ◽  
Wen Li ◽  
Zhenghong Chen ◽  
Sizhe Gao ◽  
Wei Hong ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Point Mutations ◽  
23S Rrna ◽  
Bifunctional Enzyme ◽  
Key Factors ◽  
Content Type ◽  
Bacterial Drug Resistance ◽  
Resistant Strains ◽  
H Pylori

ABSTRACT Clarithromycin (CLA) is a commonly recommended drug for Helicobacter pylori eradication. However, the prevalence of CLA-resistant H. pylori is increasing. Although point mutations in the 23S rRNA are key factors for CLA resistance, other factors, including efflux pumps and regulation genes, are also involved in the resistance of H. pylori to CLA. Guanosine 3′-diphosphate 5′-triphosphate and guanosine 3′,5′-bispyrophosphate [(p)ppGpp)], which are synthesized by the bifunctional enzyme SpoT in H. pylori, play an important role for some bacteria to adapt to antibiotic pressure. Nevertheless, no related research involving H. pylori has been reported. In addition, transporters have been found to be related to bacterial drug resistance. Therefore, this study investigated the function of SpoT in H. pylori resistance to CLA by examining the shifts in the expression of transporters and explored the role of transporters in the CLA resistance of H. pylori. A ΔspoT strain was constructed in this study, and it was shown that SpoT is involved in H. pylori tolerance of CLA by upregulating the transporters HP0939, HP1017, HP0497, and HP0471. This was assessed using a series of molecular and biochemical experiments and a cDNA microarray. Additionally, the knockout of genes hp0939, hp0471, and hp0497 in the resistant strains caused a reduction or loss (the latter in the Δhp0497 strain) of resistance to CLA. Furthermore, the average expression levels of these four transporters in clinical CLA-resistant strains were considerably higher than those in clinical CLA-sensitive strains. Taken together, our results revealed a novel molecular mechanism of H. pylori adaption to CLA stress.

scholarly journals Proregenerative Activity of IL-33 in Gastric Tissue Cells Undergoing Helicobacter Pylori-Induced Apoptosis

2020 ◽  
Vol 21 (5) ◽  
pp. 1801
Author(s):  
Weronika Gonciarz ◽  
Agnieszka Krupa ◽  
Magdalena Chmiela
Keyword(s):  
Helicobacter Pylori ◽  
Metabolic Activity ◽  
Tissue Cell ◽  
Host Immune System ◽  
Gastric Tissue ◽  
Antigenic Complex ◽  
H Pylori ◽  
Induced Apoptosis

Interleukin (IL)-33 is a proinflammatory mediator that alerts the host immune system to disorders in tissue homeostasis. Aim. To understand the role of IL-33 in modulating gastric tissue cell growth affected by Helicobacter pylori (H. pylori). Methods. IL-33 production in guinea pigs (Caviae porcellus) experimentally infected with H. pylori was evaluated by ELISA or immunohistochemical staining. The proregenerative activity of IL-33 was evaluated using gastric epithelial cells and fibroblasts that were naive or transfected with IL-33 siRNA exposed to H. pylori glycine acid extract antigenic complex (GE), as well as by measuring cell migration, proliferation, metabolic activity and apoptosis. Animals infected by H. pylori responded with increased production of IL-33. Also, cells treated in vitro with GE released more IL-33 than cells that were unstimulated. Silencing IL-33 in cells resulted in downregulation of metabolic activity, adhesion, migration and proliferation, especially after treatment with H. pylori GE, as well as upregulation of cells apoptosis associated with caspase 3 increase and Bcl-xL decrease, suggesting proregenerative activity of IL-33. Interestingly, upregulation of cell proliferation by IL-33 was Erk independent. Our results indicate that IL-33 may protect gastric tissue from loss of homeostasis caused by deleterious effects of H. pylori components and the inflammatory response developed during infection.

scholarly journals Interleukin-17C in Human Helicobacter pylori Gastritis

2017 ◽  
Vol 85 (10) ◽  
Author(s):  
Shingo Tanaka ◽  
Hiroyuki Nagashima ◽  
Modesto Cruz ◽  
Tomohisa Uchida ◽  
Takahiro Uotani ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Gastric Biopsy ◽  
Interleukin 17 ◽  
Human Gastric Mucosa ◽  
Mrna Levels ◽  
Content Type ◽  
Biopsy Specimens ◽  
H Pylori

ABSTRACT The interleukin-17 (IL-17) family of cytokines (IL-17A to IL-17F) is involved in many inflammatory diseases. Although IL-17A is recognized as being involved in the pathophysiology of Helicobacter pylori-associated diseases, the role of other IL-17 cytokine family members remains unclear. Microarray analysis of IL-17 family cytokines was performed in H. pylori-infected and uninfected gastric biopsy specimens. IL-17C mRNA was upregulated approximately 4.5-fold in H. pylori-infected gastric biopsy specimens. This was confirmed by quantitative reverse transcriptase PCR in infected and uninfected gastric mucosa obtained from Bhutan and from the Dominican Republic. Immunohistochemical analysis showed that IL-17C expression in H. pylori-infected gastric biopsy specimens was predominantly localized to epithelial and chromogranin A-positive endocrine cells. IL-17C mRNA levels were also significantly greater among cagA-positive than cagA-negative H. pylori infections (P = 0.012). In vitro studies confirmed an increase in IL-17C mRNA and protein levels in cells infected with cagA-positive infections compared to cells infected with either cagA-negative or cag pathogenicity island (PAI) mutant. Chemical inhibition of IκB kinase (IKK), mitogen-activated protein extracellular signal-regulated kinase (MEK), and Jun N-terminal kinase (JNK) inhibited induction of IL-17C proteins in infected cells, whereas p38 inhibition had no effect on IL-17C protein secretion. In conclusion, H. pylori infection was associated with a significant increase in IL-17C expression in human gastric mucosa. The role of IL-17C in the pathogenesis of H. pylori-induced diseases remains to be determined.

scholarly journals Evaluation of miR-21 Expression Level in Helicobacter pylori-Infected Gastric Mucosa

2020 ◽  
Vol 13 (7) ◽  
Author(s):  
Mona Noohi ◽  
Mojdeh Hakemi-Vala ◽  
Jamileh Nowroozi ◽  
Seyed Reza Fatemi ◽  
Mehrouz Dezfulian
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Internal Control ◽  
Expression Level ◽  
Rt Pcr ◽  
Mucosal Tissues ◽  
Dyspeptic Symptoms ◽  
H Pylori ◽  
U6 Gene

Background: Gastric cancer is one of the main causes of death worldwide. In this regard, Helicobacter pylori infection is considered as the main risk factor for gastric cancer. MicroRNA (mirNA) can interface with mRNA molecules as well as blocking their translation into proteins or inducing degradation. Objectives: The aim of this study was to compare the expression of mir-21 in biopsy samples of gastritis and healthy adjacent tissues. Methods: Between Feb-Dec 2017, 70 patients with dyspeptic symptoms from Taleghani Hospital were enrolled in this study. Accordingly, the expression level of mir-21 was evaluated using semi-quantitative RT-PCR in mucosal biopsy samples from those well-characterized patients. Moreover, the U6 gene was used as an internal control. Results: Our data indicated that mir-21 expression was significantly up-regulated in the infected samples with H. pylori compared to healthy samples. Conclusions: Our results confirm that H. pylori infection can alter the expression of mir-21 in gastric epithelial cells and gastric mucosal tissues. However, the exact role of the miRNA changes in H. pylori infection will require further experiments.

scholarly journals Role of Energy Sensor TlpD of Helicobacter pylori in Gerbil Colonization and Genome Analyses after Adaptation in the Gerbil

2013 ◽  
Vol 81 (10) ◽  
pp. 3534-3551 ◽  
Author(s):  
Wiebke Behrens ◽  
Tobias Schweinitzer ◽  
Joena Bal ◽  
Martina Dorsch ◽  
André Bleich ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Human Isolate ◽  
Infection Model ◽  
Energy Yield ◽  
Content Type ◽  
Full Characterization ◽  
H Pylori ◽  
The Impact

ABSTRACTHelicobacter pylorimaintains colonization in its human host using a limited set of taxis sensors. TlpD is a proposed energy taxis sensor ofH. pyloriand dominant under environmental conditions of low bacterial energy yield. We studied the impact ofH. pyloriTlpD on colonizationin vivousing a gerbil infection model which closely mimics the gastric physiology of humans. A gerbil-adaptedH. pyloristrain, HP87 P7, showed energy-dependent behavior, while its isogenictlpDmutant lost it. A TlpD-complemented strain regained the wild-type phenotype. Infection of gerbils with the complemented strain demonstrated that TlpD is important for persistent infection in the antrum and corpus and suggested a role of TlpD in horizontal navigation and persistent corpus colonization. As a part of the full characterization of the model and to gain insight into the genetic basis ofH. pyloriadaptation to the gerbil, we determined the complete genome sequences of the gerbil-adapted strain HP87 P7, two HP87 P7tlpDmutants before and after gerbil passage, and the original human isolate, HP87. The integrity of the genome, including that of a functionalcagpathogenicity island, was maintained after gerbil adaptation. Genetic and phenotypic differences between the strains were observed. Major differences between the gerbil-adapted strain and the human isolate emerged, including evidence of recent recombination. Passage of thetlpDmutant through the gerbil selected for gain-of-function variation in a fucosyltransferase gene,futC(HP0093). In conclusion, a gerbil-adaptedH. pyloristrain with a stable genome has helped to establish that TlpD has important functions for persistent colonization in the stomach.

scholarly journals Divergent Mechanisms of Interaction of Helicobacter pylori and Campylobacter jejuni with Mucus and Mucins

2013 ◽  
Vol 81 (8) ◽  
pp. 2838-2850 ◽  
Author(s):  
Julie Ann Naughton ◽  
Karina Mariño ◽  
Brendan Dolan ◽  
Colm Reid ◽  
Ronan Gough ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Campylobacter Jejuni ◽  
Microarray Platform ◽  
Parental Cell ◽  
Content Type ◽  
Intestinal Mucus ◽  
Proximal Small Intestine ◽  
Glycolipid Fraction ◽  
H Pylori

ABSTRACTHelicobacter pyloriandCampylobacter jejunicolonize the stomach and intestinal mucus, respectively. Using a combination of mucus-secreting cells, purified mucins, and a novel mucin microarray platform, we examined the interactions of these two organisms with mucus and mucins.H. pyloriandC. jejunibound to distinctly different mucins.C. jejunidisplayed a striking tropism for chicken gastrointestinal mucins compared to mucins from other animals and preferentially bound mucins from specific avian intestinal sites (in order of descending preference: the large intestine, proximal small intestine, and cecum).H. pyloribound to a number of animal mucins, including porcine stomach mucin, but with less avidity than that ofC. jejunifor chicken mucin. The strengths of interaction of various wild-type strains ofH. pyloriwith different animal mucins were comparable, even though they did not all express the same adhesins. The production of mucus by HT29-MTX-E12 cells promoted higher levels of infection byC. jejuniandH. pylorithan those for the non-mucus-producing parental cell lines. BothC. jejuniandH. pyloribound to HT29-MTX-E12 mucus, and while both organisms bound to glycosylated epitopes in the glycolipid fraction of the mucus, onlyC. jejunibound to purified mucin. This study highlights the role of mucus in promoting bacterial infection and emphasizes the potential for even closely related bacteria to interact with mucus in different ways to establish successful infections.

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