scholarly journals Outer Membrane Vesicle Production by Helicobacter pylori Represents an Approach for the Delivery of Virulence Factors CagA, VacA and UreA into Human Gastric Adenocarcinoma (AGS) Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 3942
Author(s):  
Yongyu Chew ◽  
Hsin-Yu Chung ◽  
Po-Yi Lin ◽  
Deng-Chyang Wu ◽  
Shau-Ku Huang ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Outer Membrane ◽  
Gastric Adenocarcinoma ◽  
Virulence Factors ◽  
Outer Membrane Vesicles ◽  
Host Cells ◽  
Ags Cells ◽  
Α Subunit ◽  
Human Gastric Adenocarcinoma ◽  
H Pylori

Helicobacter pylori infection is the etiology of several gastric-related diseases including gastric cancer. Cytotoxin associated gene A (CagA), vacuolating cytotoxin A (VacA) and α-subunit of urease (UreA) are three major virulence factors of H. pylori, and each of them has a distinct entry pathway and pathogenic mechanism during bacterial infection. H. pylori can shed outer membrane vesicles (OMVs). Therefore, it would be interesting to explore the production kinetics of H. pylori OMVs and its connection with the entry of key virulence factors into host cells. Here, we isolated OMVs from H. pylori 26,695 strain and characterized their properties and interaction kinetics with human gastric adenocarcinoma (AGS) cells. We found that the generation of OMVs and the presence of CagA, VacA and UreA in OMVs were a lasting event throughout different phases of bacterial growth. H. pylori OMVs entered AGS cells mainly through macropinocytosis/phagocytosis. Furthermore, CagA, VacA and UreA could enter AGS cells via OMVs and the treatment with H. pylori OMVs would cause cell death. Comparison of H. pylori 26,695 and clinical strains suggested that the production and characteristics of OMVs are not only limited to laboratory strains commonly in use, but a general phenomenon to most H. pylori strains.

scholarly journals Helicobacter pylori Outer Membrane Vesicles and Extracellular Vesicles from Helicobacter pylori-Infected Cells in Gastric Disease Development

2021 ◽  
Vol 22 (9) ◽  
pp. 4823
Author(s):  
María Fernanda González ◽  
Paula Díaz ◽  
Alejandra Sandoval-Bórquez ◽  
Daniela Herrera ◽  
Andrew F. G. Quest
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Outer Membrane ◽  
Extracellular Vesicles ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Host Cells ◽  
Gastric Epithelium ◽  
Infected Cells ◽  
H Pylori

Extracellular vesicles (EVs) are cell-derived vesicles important in intercellular communication that play an essential role in host-pathogen interactions, spreading pathogen-derived as well as host-derived molecules during infection. Pathogens can induce changes in the composition of EVs derived from the infected cells and use them to manipulate their microenvironment and, for instance, modulate innate and adaptive inflammatory immune responses, both in a stimulatory or suppressive manner. Gastric cancer is one of the leading causes of cancer-related deaths worldwide and infection with Helicobacter pylori (H. pylori) is considered the main risk factor for developing this disease, which is characterized by a strong inflammatory component. EVs released by host cells infected with H. pylori contribute significantly to inflammation, and in doing so promote the development of disease. Additionally, H. pylori liberates vesicles, called outer membrane vesicles (H. pylori-OMVs), which contribute to atrophia and cell transformation in the gastric epithelium. In this review, the participation of both EVs from cells infected with H. pylori and H. pylori-OMVs associated with the development of gastric cancer will be discussed. By deciphering which functions of these external vesicles during H. pylori infection benefit the host or the pathogen, novel treatment strategies may become available to prevent disease.

scholarly journals Helicobacter pylori-Derived Outer Membrane Vesicles (OMVs): Role in Bacterial Pathogenesis?

2020 ◽  
Vol 8 (9) ◽  
pp. 1328 ◽  
Author(s):  
Miroslaw Jarzab ◽  
Gernot Posselt ◽  
Nicole Meisner-Kober ◽  
Silja Wessler
Keyword(s):  
Helicobacter Pylori ◽  
Outer Membrane ◽  
Current Knowledge ◽  
Membrane Vesicles ◽  
Bacterial Pathogenesis ◽  
Outer Membrane Vesicles ◽  
Host Cells ◽  
Cellular Mechanisms ◽  
Wide Range ◽  
H Pylori

Persistent infections with the human pathogen Helicobacter pylori (H. pylori) have been closely associated with the induction and progression of a wide range of gastric disorders, including acute and chronic gastritis, ulceration in the stomach and duodenum, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma. The pathogenesis of H. pylori is determined by a complicated network of manifold mechanisms of pathogen–host interactions, which involves a coordinated interplay of H. pylori pathogenicity and virulence factors with host cells. While these molecular and cellular mechanisms have been intensively investigated to date, the knowledge about outer membrane vesicles (OMVs) derived from H. pylori and their implication in bacterial pathogenesis is not well developed. In this review, we summarize the current knowledge on H. pylori-derived OMVs.

scholarly journals The Role of a Dipeptide Transporter in the Virulence of Human Pathogen, Helicobacter pylori

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaohong Xu ◽  
Junwei Chen ◽  
Xiaoxing Huang ◽  
Shunhang Feng ◽  
Xiaoyan Zhang ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Virulence Factors ◽  
Outer Membrane Proteins ◽  
Wild Type ◽  
Ags Cells ◽  
Dipeptide Transporter ◽  
Adhesion Level ◽  
H Pylori ◽  
Substrate Binding Protein

Helicobacter pylori harbors a dipeptide (Dpp) transporter consisting of a substrate-binding protein (DppA), two permeases (DppB and C), and two ATPases (DppD and F). The Dpp transporter is responsible for the transportation of dipeptides and short peptides. We found that its expression is important for the growth of H. pylori. To understand the role of the Dpp transporter in the pathogenesis of H. pylori, the expression of virulence factors and H. pylori-induced IL-8 production were investigated in H. pylori wild-type and isogenic H. pylori Dpp transporter mutants. We found that expression of CagA was downregulated, while expression of type 4 secretion system (T4SS) components was upregulated in Dpp transporter mutants. The DppA mutant strain expressed higher levels of outer membrane proteins (OMPs), including BabA, HopZ, OipA, and SabA, and showed a higher adhesion level to gastric epithelial AGS cells compared with the H. pylori 26695 wild-type strain. After infection of AGS cells, H. pylori ΔdppA induced a higher level of NF-κB activation and IL-8 production compared with wild-type. These results suggested that in addition to supporting the growth of H. pylori, the Dpp transporter causes bacteria to alter the expression of virulence factors and reduces H. pylori-induced NF-κB activation and IL-8 production in gastric epithelial cells.

scholarly journals Hesperetin Inhibits Expression of Virulence Factors and Growth of Helicobacter pylori

2021 ◽  
Vol 22 (18) ◽  
pp. 10035
Author(s):  
Hyun Woo Kim ◽  
Hyun Jun Woo ◽  
Ji Yeong Yang ◽  
Jong-Bae Kim ◽  
Sa-Hyun Kim
Keyword(s):  
Helicobacter Pylori ◽  
Virulence Factors ◽  
Gastrointestinal Diseases ◽  
Secretion System ◽  
Ags Cells ◽  
Type Iv ◽  
Inhibitory Mechanisms ◽  
Expression Of Genes ◽  
H Pylori ◽  
Type V

Helicobacter pylori (H. pylori) is a bacterium known to infect the human stomach. It can cause various gastrointestinal diseases including gastritis and gastric cancer. Hesperetin is a major flavanone component contained in citrus fruits. It has been reported to possess antibacterial, antioxidant, and anticancer effects. However, the antibacterial mechanism of hesperetin against H. pylori has not been reported yet. Therefore, the objective of this study was to determine the inhibitory effects of hesperetin on H. pylori growth and its inhibitory mechanisms. The results of this study showed that hesperetin inhibits the growth of H. pylori reference strains and clinical isolates. Hesperetin inhibits the expression of genes in replication (dnaE, dnaN, dnaQ, and holB) and transcription (rpoA, rpoB, rpoD, and rpoN) machineries of H. pylori. Hesperetin also inhibits the expression of genes related to H. pylori motility (flhA, flaA, and flgE) and adhesion (sabA, alpA, alpB, hpaA, and hopZ). It also inhibits the expression of urease. Hespereti n downregulates major virulence factors such as cytotoxin-associated antigen A (CagA) and vacuolating cytotoxin A (VacA) and decreases the translocation of CagA and VacA proteins into gastric adenocarcinoma (AGS) cells. These results might be due to decreased expression of the type IV secretion system (T4SS) and type V secretion system (T5SS) involved in translocation of CagA and VacA, respectively. The results of this study indicate that hesperetin has antibacterial effects against H. pylori. Thus, hesperetin might be an effective natural product for the eradication of H. pylori.

scholarly journals Genes of Helicobacter pylori Regulated by Attachment to AGS Cells

2004 ◽  
Vol 72 (4) ◽  
pp. 2358-2368 ◽  
Author(s):  
Nayoung Kim ◽  
Elizabeth A. Marcus ◽  
Yi Wen ◽  
David L. Weeks ◽  
David R. Scott ◽  
...  
Keyword(s):  
Gene Expression ◽  
Helicobacter Pylori ◽  
Outer Membrane ◽  
Quantitative Pcr ◽  
Stress Responses ◽  
Gastric Epithelium ◽  
Rt Pcr ◽  
Down Regulation ◽  
Ags Cells ◽  
H Pylori

ABSTRACT Reciprocal interactions between Helicobacter pylori and cells of the gastric epithelium to which it adheres may affect colonization. Changes in gene expression of H. pylori induced by adhesion to AGS gastric cancer cells by coculture were compared to changes in gene expression of H. pylori cultured without AGS cells by using cDNA filter macroarrays. Adhesion was quantitatively verified by confocal microscopy of green fluorescent protein-expressing bacteria. Four experiments showed that 22 and 21 H. pylori genes were consistently up- and down-regulated, respectively. The up-regulated genes included pathogenicity island, motility, outer membrane protein, and translational genes. The σ28 factor antagonist flgM, flgG, the stress response gene, flaA, omp11, and the superoxide dismutase gene (sodB) were down-regulated. The up-regulation of cag3, flgB, tonB, rho, and deaD was confirmed by quantitative PCR, and the up-regulation of lpxD, omp6, secG, fabH, HP1285, HP0222, and HP0836 was confirmed by reverse transcription (RT)-PCR. The down-regulation of flaA, sodB, and HP0874 was confirmed by quantitative PCR, and the down-regulation of omp11 was confirmed by RT-PCR. The alteration of gene expression in H. pylori after adhesion to gastric cells in vitro suggests that changes in motility, outer membrane composition, and stress responses, among other changes, may be involved in gastric colonization.

scholarly journals Chemokines and Antimicrobial Peptides Have acag-Dependent Early Response to Helicobacter pylori Infection in Primary Human Gastric Epithelial Cells

2014 ◽  
Vol 82 (7) ◽  
pp. 2881-2889 ◽  
Author(s):  
Pascale Mustapha ◽  
Isabelle Paris ◽  
Magali Garcia ◽  
Cong Tri Tran ◽  
Julie Cremniter ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Antimicrobial Peptides ◽  
Virulence Factors ◽  
Inflammatory Mediator ◽  
Host Cells ◽  
Gastric Epithelial Cells ◽  
Content Type ◽  
H Pylori

ABSTRACTHelicobacter pyloriinfection systematically causes chronic gastric inflammation that can persist asymptomatically or evolve toward more severe gastroduodenal pathologies, such as ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. Thecagpathogenicity island (cagPAI) ofH. pyloriallows translocation of the virulence protein CagA and fragments of peptidoglycan into host cells, thereby inducing production of chemokines, cytokines, and antimicrobial peptides. In order to characterize the inflammatory response toH. pylori, a new experimental protocol for isolating and culturing primary human gastric epithelial cells was established using pieces of stomach from patients who had undergone sleeve gastrectomy. Isolated cells expressed markers indicating that they were mucin-secreting epithelial cells. Challenge of primary epithelial cells withH. pyloriB128 underscored early dose-dependent induction of expression of mRNAs of the inflammatory mediators CXCL1 to -3, CXCL5, CXCL8, CCL20, BD2, and tumor necrosis factor alpha (TNF-α). In AGS cells, significant expression of only CXCL5 and CXCL8 was observed following infection, suggesting that these cells were less reactive than primary epithelial cells. Infection of both cellular models withH. pyloriB128ΔcagM, acagPAI mutant, resulted in weak inflammatory-mediator mRNA induction. At 24 h after infection of primary epithelial cells withH. pylori, inflammatory-mediator production was largely due tocagPAI substrate-independent virulence factors. Thus,H. pyloricagPAI substrate appears to be involved in eliciting an epithelial response during the early phases of infection. Afterwards, other virulence factors of the bacterium take over in development of the inflammatory response. Using a relevant cellular model, this study provides new information on the modulation of inflammation duringH. pyloriinfection.

Helicobacter pylori-induced H,K-ATPase α-subunit gene repression is mediated by NF-κB p50 homodimer promoter binding

2008 ◽  
Vol 294 (3) ◽  
pp. G795-G807 ◽  
Author(s):  
Arindam Saha ◽  
Charles E. Hammond ◽  
Maria Trojanowska ◽  
Adam J. Smolka
Keyword(s):  
Helicobacter Pylori ◽  
Mapk Pathway ◽  
Point Mutations ◽  
Gastric Body ◽  
Ags Cells ◽  
Α Subunit ◽  
Cell Enzyme ◽  
Dna Protein Interaction ◽  
H Pylori ◽  
Interfering Rna

Infection of human gastric body mucosa by the gram-negative, microaerophilic bacterium Helicobacter pylori induces an inflammatory response and a transitory hypochlorhydria that progresses in ∼2% of patients to atrophic gastritis, dysplasia, and gastric adenocarcinoma. We have previously shown that H. pylori infection of cultured gastric epithelial cells (AGS) represses the activity of the transfected α-subunit (HKα) promoter of H,K-ATPase, the parietal cell enzyme mediating acid secretion. However, the mechanistic details of H. pylori-mediated repression of HKα and ensuing hypochlorhydria are unknown. H. pylori is known to upregulate the transcription factor NF-κB through the ERK1/2 MAPK pathway. We identified NF-κB-binding regions in the HKα promoter and found that H. pylori inoculation of AGS cells increased NF-κB p50 binding to the transfected HKα promoter and repressed its transcriptional activity. Immunoblot and DNA-protein interaction studies showed that although active phosphorylated NF-κB p65 is present in H. pylori-infected AGS cells, an NF-κB p50/p65 heterodimeric complex fails to bind to the HKα promoter. Point mutations at −159 and −161 bp in the HKα promoter NF-κB binding sequence prevented binding of NF-κB p50 and prevented H. pylori repression of point-mutated HKα promoter activity in transfected AGS cells. Small interfering RNA-mediated knockdown of NF-κB p50 in H. pylori-infected AGS cells also abrogated H. pylori-induced HKα repression, whereas NF-κB p65 knockdown did not. We conclude that H. pylori inhibits HKα gene expression by ERK1/2-mediated NF-κB p50 homodimer binding to the HKα promoter. This study identifies a novel pathogen-dependent mechanism of H,K-ATPase inhibition and contributes to understanding of H. pylori pathophysiology.

scholarly journals Evodiamine Inhibits Helicobacter pylori Growth and Helicobacter pylori-Induced Inflammation

2021 ◽  
Vol 22 (7) ◽  
pp. 3385
Author(s):  
Ji Yeong Yang ◽  
Jong-Bae Kim ◽  
Pyeongjae Lee ◽  
Sa-Hyun Kim
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Secretion System ◽  
Host Cells ◽  
World Health ◽  
Ags Cells ◽  
Inhibitory Mechanisms ◽  
Anti Inflammatory ◽  
H Pylori ◽  
Bacterial Effect

Helicobacter pylori (H. pylori) classified as a class I carcinogen by the World Health Organization (WHO) plays an important role in the progression of chronic gastritis and the development of gastric cancer. A major bioactive component of Evodia rutaecarpa, evodiamine, has been known for its anti-bacterial effect and anti-cancer effects. However, the inhibitory effect of evodiamine against H. pylori is not yet known and the inhibitory mechanisms of evodiamine against gastric cancer cells are yet to be elucidated concretely. In this study, therefore, anti-bacterial effect of evodiamine on H. pylori growth and its inhibitory mechanisms as well as anti-inflammatory effects and its mechanisms of evodiamine on H. pylori-induced inflammation were investigated in vitr. Results of this study showed the growth of the H. pylori reference strains and clinical isolates were inhibited by evodiamine. It was considered one of the inhibitory mechanisms that evodiamine downregulated both gene expressions of replication and transcription machineries of H. pylori. Treatment of evodiamine also induced downregulation of urease and diminished translocation of cytotoxin-associated antigen A (CagA) and vacuolating cytotoxin A (VacA) proteins into gastric adenocarcinoma (AGS) cells. This may be resulted from the reduction of CagA and VacA expressions as well as the type IV secretion system (T4SS) components and secretion system subunit protein A (SecA) protein which are involved in translocation of CagA and VacA into host cells, respectively. In particular, evodiamine inhibited the activation of signaling proteins such as the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and the mitogen-activated protein kinase (MAPK) pathway induced by H. pylori infection. It consequently might contribute to reduction of interleukin (IL)-8 production in AGS cells. Collectively, these results suggest anti-bacterial and anti-inflammatory effects of evodiamine against H. pylori.

scholarly journals Outer Membrane Vesicles Secreted by Helicobacter pylori Transmitting Gastric Pathogenic Virulence Factors

ACS Omega ◽  
2021 ◽  
Author(s):  
Sisi Wei ◽  
Xiaoya Li ◽  
Jingjing Wang ◽  
Yaojie Wang ◽  
Cong Zhang ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Outer Membrane ◽  
Virulence Factors ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles

scholarly journals Selective Inhibition of Helicobacter pylori Carbonic Anhydrases by Carvacrol and Thymol Could Impair Biofilm Production and the Release of Outer Membrane Vesicles

2021 ◽  
Vol 22 (21) ◽  
pp. 11583
Author(s):  
Rossella Grande ◽  
Simone Carradori ◽  
Valentina Puca ◽  
Irene Vitale ◽  
Andrea Angeli ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Outer Membrane ◽  
Bacterial Resistance ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Peptic Ulcers ◽  
Carbonic Anhydrases ◽  
Biofilm Production ◽  
Isoform Selectivity ◽  
H Pylori

Helicobacter pylori, a Gram-negative neutrophilic pathogen, is the cause of chronic gastritis, peptic ulcers, and gastric cancer in humans. Current therapeutic regimens suffer from an emerging bacterial resistance rate and poor patience compliance. To improve the discovery of compounds targeting bacterial alternative enzymes or essential pathways such as carbonic anhydrases (CAs), we assessed the anti-H. pylori activity of thymol and carvacrol in terms of CA inhibition, isoform selectivity, growth impairment, biofilm production, and release of associated outer membrane vesicles-eDNA. The microbiological results were correlated by the evaluation in vitro of H. pylori CA inhibition, in silico analysis of the structural requirements to display such isoform selectivity, and the assessment of their limited toxicity against three probiotic species with respect to amoxicillin. Carvacrol and thymol could thus be considered as new lead compounds as alternative H. pylori CA inhibitors or to be used in association with current drugs for the management of H. pylori infection and limiting the spread of antibiotic resistance.

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