Intrafamilial Infection of Helicobacter Pylori: Abnormal Gastric Epithelial Cells, Pedestal-Rich H. Pylori Adherence, and a Gene Mutation in a Child with Protein-Losing Gastroenteropathy

2019 ◽  
Vol 2 (3) ◽  
pp. 83-99
Author(s):  
T.W. Wan ◽  
O. Khokhlova ◽  
W. Higuchi ◽  
I. Protasova ◽  
Olga V. Peryanova ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Epithelial Cells ◽  
Gene Mutation ◽  
Virulence Factor ◽  
East Asian ◽  
Gastric Epithelium ◽  
Gastric Epithelial Cells ◽  
H Pylori

Abstract Helicobacter pylori, one of the most prevalent human pathogens, colonizes the gastric mucosa and is associated with gastric diseases, such as gastritis and peptic ulcers, and is also a bacterial risk factor for gastric cancer. Cytotoxin-associated gene A (CagA) protein, a major virulence factor of H. pylori, is phosphorylated in cells at its Glu-Pro-IIe-Tyr-Ala (EPIYA) motif and is considered to trigger gastric cancer. CagA is classified into two forms, Western CagA with EPIYA-ABC and East Asian CagA with EPIYA-ABD, with the latter associated with a high risk of developing gastric cancer. CagA causes morphological transformation of cells, yielding the “hummingbird” phenotype in AGS cells and possibly membranous pedestals in the gastric epithelium, albeit rarely. H. pylori adherence to the gastric mucosa is not yet fully understood. Here, we describe an intrafamilial infection case of H. pylori, focusing on the gastric epithelium, H. pylori adherence, and a gene mutation in a child with protein-losing gastroenteropathy (characterized by excessive loss of plasma proteins into the gastrointestinal tract). H. pylori, which also infected family members (mother and father), was genetically a single clone with the virulence genes of an East Asian type. The patient’ gastric mucosa exhibited some unique features. Endoscopy revealed the presence of protein plugs on the mucosal surface, which were immunoelectrophoretically similar to serum proteins. Electron microscopy revealed abnormal gastric epithelial cells, totally covered with the secretions or possessing small swollen structures and irregular microvilli. The patient’s H. pylori infection was characterized by frequently occurring thick pedestals, formed along adherent H. pylori. The serum protein level returned to normal and the protein plugs disappeared after the successful eradication of H. pylori, albeit with lag periods for healing. He had a mutation in the OCRL1 gene, associated with Dent disease (asymptomatic proteinuria). Thus, in the patient’s gastric mucosa, we found the abnormal gastric epithelial cells, which may be caused by an OCRL1 mutation or H. pylori, and pedestal-rich H. pylori infection, possibly caused by a higher level of action of CagA in the abnormal epithelial cells. The data suggests a novel H. pylori virulence factor associated with “excessive plasma protein release”.

scholarly journals Expression of the Programmed Death Ligand 1, B7-H1, on Gastric Epithelial Cells after Helicobacter pylori Exposure Promotes Development of CD4+ CD25+ FoxP3+ Regulatory T Cells

2007 ◽  
Vol 75 (9) ◽  
pp. 4334-4341 ◽  
Author(s):  
Ellen J. Beswick ◽  
Irina V. Pinchuk ◽  
Soumita Das ◽  
Don W. Powell ◽  
Victor E. Reyes
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Gastric Mucosa ◽  
Epithelial Cells ◽  
Treg Cells ◽  
T Cell Response ◽  
Gastric Epithelium ◽  
Gastric Epithelial Cells ◽  
H Pylori

ABSTRACT During Helicobacter pylori infection, T cells are recruited to the gastric mucosa, but the host T-cell response is not sufficient to clear the infection. Some of the recruited T cells respond in a polarized manner to a Th1 response, while others become anergic. We have previously shown that T-cell anergy may be induced during infection by the interaction of T cells with B7-H1, which is up-regulated on the gastric epithelium during H. pylori infection. Recently, regulatory T (Treg) cells with a CD4+ CD25high FoxP3+ phenotype were found at an increased frequency in the gastric mucosa of biopsy specimens from H. pylori-infected patients. While Treg cells are important in maintaining tolerance, they can also suppress immune responses during infection. In this study, we examined the induction of the Treg phenotype when naïve T cells were incubated with gastric epithelial cells exposed to H. pylori. The frequency of this phenotype was markedly decreased when B7-H1 was blocked with monoclonal antibodies or its expression was blocked with small interfering RNA. The functional role of these Treg cells was assessed in proliferation assays when the cells were cocultured with activated T cells, which effectively decreased proliferation of the cells.

scholarly journals Inhibitory Effect of β-Carotene on Helicobacter pylori-Induced TRAF Expression and Hyper-Proliferation in Gastric Epithelial Cells

Antioxidants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 637 ◽  
Author(s):  
Yongchae Park ◽  
Hanbit Lee ◽  
Joo Weon Lim ◽  
Hyeyoung Kim
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Nadph Oxidase ◽  
Gastric Epithelial Cells ◽  
Gastric Cancer Cells ◽  
Ags Cells ◽  
H Pylori ◽  
Β Carotene

Helicobacter pylori infection causes the hyper-proliferation of gastric epithelial cells that leads to the development of gastric cancer. Overexpression of tumor necrosis factor receptor associated factor (TRAF) is shown in gastric cancer cells. The dietary antioxidant β-carotene has been shown to counter hyper-proliferation in H. pylori-infected gastric epithelial cells. The present study was carried out to examine the β-carotene mechanism of action. We first showed that H. pylori infection decreases cellular IκBα levels while increasing cell viability, NADPH oxidase activity, reactive oxygen species production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and TRAF1 and TRAF2 gene expression, as well as protein–protein interaction in gastric epithelial AGS cells. We then demonstrated that pretreatment of cells with β-carotene significantly attenuates these effects. Our findings support the proposal that β-carotene has anti-cancer activity by reducing NADPH oxidase-mediated production of ROS, NF-κB activation and NF-κB-regulated TRAF1 and TRAF2 gene expression, and hyper-proliferation in AGS cells. We suggest that the consumption of β-carotene-enriched foods could decrease the incidence of H. pylori-associated gastric disorders.

scholarly journals Phylogeographic Origin of Helicobacter pylori Determines Host-Adaptive Responses upon Coculture with Gastric Epithelial Cells

2013 ◽  
Vol 81 (7) ◽  
pp. 2468-2477 ◽  
Author(s):  
Alexander Sheh ◽  
Rupesh Chaturvedi ◽  
D. Scott Merrell ◽  
Pelayo Correa ◽  
Keith T. Wilson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Gastric Disease ◽  
Gastric Epithelial Cells ◽  
Gastric Cancer Risk ◽  
Content Type ◽  
H Pylori ◽  
Induced Apoptosis

ABSTRACTWhileHelicobacter pyloriinfects over 50% of the world's population, the mechanisms involved in the development of gastric disease are not fully understood. Bacterial, host, and environmental factors play a role in disease outcome. To investigate the role of bacterial factors inH. pyloripathogenesis, global gene expression of sixH. pyloriisolates was analyzed during coculture with gastric epithelial cells. Clustering analysis of six Colombian clinical isolates from a region with low gastric cancer risk and a region with high gastric cancer risk segregated strains based on their phylogeographic origin. One hundred forty-six genes had increased expression in European strains, while 350 genes had increased expression in African strains. Differential expression was observed in genes associated with motility, pathogenicity, and other adaptations to the host environment. European strains had greater expression of the virulence factorscagA,vacA, andbabBand were associated with increased gastric histologic lesions in patients. In AGS cells, European strains promoted significantly higher interleukin-8 (IL-8) expression than did African strains. African strains significantly induced apoptosis, whereas only one European strain significantly induced apoptosis. Our data suggest that gene expression profiles of clinical isolates can discriminate strains by phylogeographic origin and that these profiles are associated with changes in expression of the proinflammatory and protumorigenic cytokine IL-8 and levels of apoptosis in host epithelial cells. These findings support the hypothesis that bacterial factors determined by the phylogeographic origin ofH. pyloristrains may promote increased gastric disease.

scholarly journals Helicobacter pylori Colonization Drives Urokinase Receptor (uPAR) Expression in Murine Gastric Epithelium During Early Pathogenesis

2020 ◽  
Vol 8 (7) ◽  
pp. 1019
Author(s):  
Warner Alpízar-Alpízar ◽  
Mette E. Skindersoe ◽  
Lone Rasmussen ◽  
Mette C. Kriegbaum ◽  
Ib J. Christensen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Protein Expression ◽  
De Novo ◽  
Urokinase Receptor ◽  
Gastric Epithelium ◽  
Upar Expression ◽  
H Pylori

(1) Background: Persistent Helicobacter pylori infection is the most important risk factor for gastric cancer. The urokinase receptor (uPAR) is upregulated in lesions harboring cancer invasion and inflammation. Circumstantial evidence tends to correlate H. pylori colonization with increased uPAR expression in the human gastric epithelium, but a direct causative link has not yet been established in vivo; (2) Methods: In a mouse model of H. pylori-induced gastritis, we investigated the temporal emergence of uPAR protein expression in the gastric mucosa in response to H. pylori (SS1 strain) infection; (3) Results: We observed intense uPAR immunoreactivity in foveolar epithelial cells of the gastric corpus due to de novo synthesis, compared to non-infected animals. This uPAR induction represents a very early response, but it increases progressively over time as do infiltrating immune cells. Eradication of H. pylori infection by antimicrobial therapy causes a regression of uPAR expression to its physiological baseline levels. Suppression of the inflammatory response by prostaglandin E2 treatment attenuates uPAR expression. Notwithstanding this relationship, H. pylori does induce uPAR expression in vitro in co-cultures with gastric cancer cell lines; (4) Conclusions: We showed that persistent H. pylori colonization is a necessary event for the emergence of a relatively high uPAR protein expression in murine gastric epithelial cells.

Aberrant CpG Island Hypermethylation in Pediatric Gastric Mucosa in Association With Helicobacter pylori Infection

2011 ◽  
Vol 135 (6) ◽  
pp. 759-765
Author(s):  
So-Hyun Shin ◽  
Seog-Yun Park ◽  
Jae-Sung Ko ◽  
Nayoung Kim ◽  
Gyeong Hoon Kang
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Epithelial Cells ◽  
Cpg Island ◽  
Methylation Status ◽  
Helicobacter Pylori Infection ◽  
Gastric Epithelial Cells ◽  
Infected Adult ◽  
H Pylori ◽  
Methylight Assay

Abstract Context.—Helicobacter pylori infection is primarily acquired during childhood and persists throughout life in the absence of eradication with antibiotics. Helicobacter pylori infection induces methylation in the promoter CpG island loci in gastric epithelial cells. Thus, aberrant CpG island hypermethylation in gastric epithelial cells likely occurs early in life, although there are no existing data supporting this notion. Objectives.—To identify whether aberrant CpG island hypermethylation occurs in pediatric stomach mucosa in association with H pylori infection and to compare methylation profiles of samples from pediatric and adult stomach tissues. Design.—We analyzed pediatric (n  =  47) and adult (n  =  38) gastric mucosa samples for their methylation status in 12 promoter CpG island loci using the MethyLight assay and compared the number of methylated genes and the methylation levels in individual genes between H pylori–positive and H pylori–negative sample results and between pediatric and adult samples. Results.—The average number of methylated genes was significantly higher in H pylori–infected pediatric samples than in H pylori–negative pediatric samples (3.4 versus 0.3, P < .001) and in H pylori–infected adult samples than in H pylori–negative adult samples (7.6 versus 0.9, P < .001). Seven genes showed significantly higher methylation levels in H pylori–infected pediatric samples than in H pylori–negative pediatric samples (all values were P < .05). Conclusions.—These results indicate that CpG island hypermethylation occurs in pediatric gastric mucosa in association with H pylori infection and that the genes affected by H pylori–associated hypermethylation were similar in pediatric and adult samples.

scholarly journals Increased expression of the urokinase plasminogen activator system by Helicobacter pylori in gastric epithelial cells

2008 ◽  
Vol 295 (3) ◽  
pp. G431-G441 ◽  
Author(s):  
Susan Kenny ◽  
Cedric Duval ◽  
Stephen J. Sammut ◽  
Islay Steele ◽  
D. Mark Pritchard ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Plasminogen Activator ◽  
Egf Receptor ◽  
Gastric Epithelial Cells ◽  
Epithelial Cell Proliferation ◽  
H Pylori ◽  
Pai 1

The gastric pathogen Helicobacter pylori ( H. pylori) is linked to peptic ulcer and gastric cancer, but the relevant pathophysiological mechanisms are unclear. We now report that H. pylori stimulates the expression of plasminogen activator inhibitor (PAI)-1, urokinase plasminogen activator (uPA), and its receptor (uPAR) in gastric epithelial cells and the consequences for epithelial cell proliferation. Real-time PCR of biopsies from gastric corpus, but not antrum, showed significantly increased PAI-1, uPA, and uPAR in H. pylori-positive patients. Transfection of primary human gastric epithelial cells with uPA, PAI-1, or uPAR promoters in luciferase reporter constructs revealed expression of all three in H+/K+ATPase- and vesicular monoamine transporter 2-expressing cells; uPA was also expressed in pepsinogen- and uPAR-containing trefoil peptide-1-expressing cells. In each case expression was increased in response to H. pylori and for uPA, but not PAI-1 or uPAR, required the virulence factor CagE. H. pylori also stimulated soluble and cell surface-bound uPA activity, and both were further increased by PAI-1 knockdown, consistent with PAI-1 inhibition of endogenous uPA. H. pylori stimulated epithelial cell proliferation, which was inhibited by uPA immunoneutralization and uPAR knockdown; exogenous uPA also stimulated proliferation that was further increased after PAI-1 knockdown. The proliferative effects of uPA were inhibited by immunoneutralization of the EGF receptor and of heparin-binding EGF (HB-EGF) by the mutant diphtheria toxin CRM197 and an EGF receptor tyrosine kinase inhibitor. H. pylori induction of uPA therefore leads to epithelial proliferation through activation of HB-EGF and is normally inhibited by concomitant induction of PAI-1; treatments directed at inhibition of uPA may slow the progression to gastric cancer.

scholarly journals Helicobacter pylori Induces RANTES through Activation of NF-κB

2003 ◽  
Vol 71 (7) ◽  
pp. 3748-3756 ◽  
Author(s):  
Naoki Mori ◽  
Alan M. Krensky ◽  
Romas Geleziunas ◽  
Akihiro Wada ◽  
Toshiya Hirayama ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Epithelial Cells ◽  
Intracellular Signaling ◽  
Interleukin 1 ◽  
Luciferase Reporter ◽  
Transcriptional Level ◽  
Gastric Epithelial Cells ◽  
Rantes Promoter ◽  
H Pylori

ABSTRACT Helicobacter pylori-infected gastric mucosa displays a conspicuous infiltration of mononuclear cells and neutrophils. RANTES (short for “regulated upon activation, normal T cell expressed and secreted”) is a chemoattractant cytokine (chemokine) important in the infiltration of T lymphocytes and monocytes. RANTES may therefore contribute to the cellular infiltrate in the H. pylori-infected gastric mucosa. The aim of this study was to analyze the molecular mechanism responsible for H. pylori-mediated RANTES expression. We observed that gastric epithelial cells produced RANTES upon coculture with H. pylori. In addition, H. pylori induced RANTES mRNA expression and an increase in luciferase activity in cells which were transfected with a luciferase reporter construct derived from the RANTES promoter, in gastric epithelial cells, indicating that the induction of RANTES production occurred at the transcriptional level. Induction of RANTES was dependent on an intact cag pathogenicity island. Activation of the RANTES promoter by H. pylori occurred through the action of NF-κB. Transfection of kinase-deficient mutants of IκB kinase (IKK) and NF-κB-inducing kinase (NIK) inhibited H. pylori-mediated RANTES activation. In contrast, tumor necrosis factor alpha- or interleukin-1/Toll-like receptor signaling molecules—such as mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1, MyD88, and interleukin-1 receptor-associated kinase—did not play a role in RANTES activation by H. pylori. Collectively, H. pylori induced NF-κB activation through an intracellular signaling pathway that involved IKK and NIK, leading to RANTES gene transcription. RANTES induction by H. pylori may play an important role in gastric inflammation.

scholarly journals Identification of Functional Interactome of Gastric Cancer Cells with Helicobacter pylori Outer Membrane Protein HpaA by HPLC-MS/MS

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Ruyue Fan ◽  
Xiurui Han ◽  
Di Xiao ◽  
Lihua He ◽  
Yanan Gong ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Membrane Protein ◽  
Outer Membrane ◽  
Cell Lines ◽  
Outer Membrane Protein ◽  
Regulation Of Transcription ◽  
Gastric Epithelial Cells ◽  
H Pylori

HpaA as an outer membrane protein of Helicobacter pylori (H. pylori) plays a significant role in the adhesion to the human stomach, but the functional relation between HpaA and gastric epithelial cells is still not clear. To screen the interaction between HpaA and cellular proteins in gastric epithelial cells, the HpaA protein from H. pylori 26695 fused with a tag (6× His) was expressed and purified successfully, the secondary structure was estimated by the Circular Dichroism (CD) spectrum, and the purified recombinant protein was used to perform the pull-down assays with gastric cancer cell lines (AGS and SGC-7901) lysates, respectively. The pull-down proteins were identified by high-performance liquid chromatography tandem mass spectrometry system (HPLC-MS/MS). A total of 9 and 13 proteins related were analyzed from AGS and SGC-7901 cell lysates, respectively. ANXA2 was considered as putative HpaA functional partner discovered from lysates of both cell lines with high score and coverage. It is hypothesized that HpaA may be involved in the biological process of regulation of transcription and nucleic acid metabolism during the adhesion of H. pylori to human gastric epithelial cells, and HpaA-binding proteins also be used as targets for the development of antiadhesion drugs against H. pylori.

scholarly journals Engagement of CEACAM1 by Helicobacter pylori HopQ Is Important for the Activation of Non-Canonical NF-κB in Gastric Epithelial Cells

2021 ◽  
Vol 9 (8) ◽  
pp. 1748
Author(s):  
Karin Taxauer ◽  
Youssef Hamway ◽  
Anna Ralser ◽  
Alisa Dietl ◽  
Karin Mink ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Surface Protein ◽  
Host Cells ◽  
Gastric Epithelial Cells ◽  
Gastric Cancer Cells ◽  
Tissue Samples ◽  
Mutant Strains ◽  
H Pylori

The gastric pathogen Helicobacter pylori infects half of the world’s population and is a major risk factor for gastric cancer development. In order to attach to human gastric epithelial cells and inject the oncoprotein CagA into host cells, H. pylori utilizes the outer membrane protein HopQ that binds to the cell surface protein CEACAM, which can be expressed on the gastric mucosa. Once bound, H. pylori activates a number of signaling pathways, including canonical and non-canonical NF-κB. We investigated whether HopQ–CEACAM interaction is involved in activating the non-canonical NF-κB signaling pathway. Different gastric cancer cells were infected with the H. pylori wild type, or HopQ mutant strains, and the activation of non-canonical NF-κB was related to CEACAM expression levels. The correlation between CEACAM levels and the activation of non-canonical NF-κB was confirmed in human gastric tissue samples. Taken together, our findings show that the HopQ–CEACAM interaction is important for activation of the non-canonical NF-κB pathway in gastric epithelial cells.

scholarly journals Helicobacter pylori and Epstein-Barr Virus Coinfection Stimulates Aggressiveness in Gastric Cancer through the Regulation of Gankyrin

mSphere ◽  
2021 ◽  
Author(s):  
Dharmendra Kashyap ◽  
Budhadev Baral ◽  
Shweta Jakhmola ◽  
Anil Kumar Singh ◽  
Hem Chandra Jha
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Epstein Barr Virus ◽  
Synergistic Effects ◽  
Gastric Epithelial Cells ◽  
Content Type ◽  
Barr Virus ◽  
Epstein Barr ◽  
H Pylori

In the present study, we evaluated the synergistic effects of EBV and H. pylori infection on gastric epithelial cells in various coinfection models. These coinfection models were among the first to depict the exposures of gastric epithelial cells to EBV followed by H. pylori ; however, coinfection models exist that narrated the scenario upon exposure to H. pylori followed by that to EBV.

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