Selective Upregulation of Endothelial E-Selectin in Response to Helicobacter pylori-Induced Gastritis

ABSTRACT Helicobacter pylori is one of the most common bacterial pathogens, infecting up to 50% of the world's population. The host is not able to clear the infection, leading to life-long chronic inflammation with continuous infiltration of lymphocytes and granulocytes. The migration of leukocytes from the blood into inflamed tissue is dependent on adhesion molecules expressed on the vascular endothelium. The aim of this study was to characterize the effect of H. pylori-induced gastritis with regard to the expression of endothelial adhesion molecules in the gastric mucosa and compare this to other types of chronic mucosal inflammations. Our results demonstrate an increased level of expression of the adhesion molecule E-selectin, but not of intracellular adhesion molecule 1, vascular adhesion molecule 1, or vascular adhesion protein 1, in H. pylori-induced gastritis but not in gastritis induced by acetylsalicylic acid or pouchitis. The upregulated E-selectin expression was determined to be localized to the gastric mucosa rather than being a systemic response to the infection. Moreover, the H. pylori type IV secretion system encoded by the cag pathogenicity island (cagPAI) was found to be an important determinant for the upregulation of human endothelial E-selectin expression in vitro, and this process is probably dependent on the CagL protein, mediating binding to α5β1 integrins. Thus, endothelial E-selectin expression induced by H. pylori probably contributes to the large influx of neutrophils and macrophages seen in infected individuals, and our results suggest that this process may be more pronounced in patients infected with cagPAI-positive H. pylori strains and may thereby contribute to tissue damage in these individuals.

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The organization of Helicobacter pylori cag-pathogenicity island (cagPAI) genes in multiracial population with histopathological changes of gastric mucosa

10.21203/rs.2.9601/v1 ◽

2019 ◽

Author(s):

Alfizah Hanafiah ◽

Shaza Azlin Razak ◽

Hui-min Neoh ◽

Noraziah Mohamad Zin ◽

Bruno S. Lopes

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Pathogenicity Island ◽

Type Iv Secretion ◽

Virulence Determinants ◽

Gastric Diseases ◽

Cag Pathogenicity Island ◽

Type Iv ◽

Inflammatory Score ◽

H Pylori

Abstract Background: Helicobacter pylori is a Gram-negative bacillus that colonises only the mucus layer of the human stomach and is implicated in gastric diseases. Virulent H. pylori harbouring cag-pathogenicity island (cagPAI) which encodes genes for type IV secretion system (T4SS) and CagA protein is one of the major virulence determinants involved in disease development. We examined the entire cagPAI genes in 95 H. pylori isolates from a multiracial population and examined the intactness of cagPAI region with histopathological scores of the gastric mucosa. Results: 95.8% of H. pylori isolates were cagPAI-positive with 23.2% having an intact cagPAI, whereas 72.6% had a partial/rearranged cagPAI. In our study, cag2 and cag4 were found to be significantly higher in H. pylori isolated from Malays, whereas cag4 was predominant in Chinese isolates. We also detected cag24 in significantly high proportion in isolates from the Malays and the Indians compared to the Chinese isolates. The intactness of cagPAI region showed an association with histopathological scores of the gastric mucosa. Significant association was observed between H. pylori harbouring partial cagPAI and higher density of H. pylori and neutrophil activity, whereas strains which lacked cagPAI was associated with higher inflammatory score. Conclusions: The screening of the entire cagPAI genes provides an accurate overview of the cagPAI organisation in H. pylori isolates in a multiracial population. The genotypes of H. pylori strains with various cagPAI rearrangement associated with patients’ ethnicities and histopathological scores might contribute to the pathogenesis of H. pylori infection in a multi-ethnic population.

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T4SS-dependent TLR5 activation by Helicobacter pylori infection

Nature Communications ◽

10.1038/s41467-019-13506-6 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

Suneesh Kumar Pachathundikandi ◽

Nicole Tegtmeyer ◽

Isabelle Catherine Arnold ◽

Judith Lind ◽

Matthias Neddermann ◽

...

Keyword(s):

Helicobacter Pylori ◽

Epithelial Cells ◽

Pathogenic Bacteria ◽

Type Iv Secretion ◽

Downstream Signaling ◽

Type Iv ◽

Efficient Control ◽

H Pylori ◽

Highly Virulent

AbstractToll-like receptor TLR5 recognizes a conserved domain, termed D1, that is present in flagellins of several pathogenic bacteria but not in Helicobacter pylori. Highly virulent H. pylori strains possess a type IV secretion system (T4SS) for delivery of virulence factors into gastric epithelial cells. Here, we show that one of the H. pylori T4SS components, protein CagL, can act as a flagellin-independent TLR5 activator. CagL contains a D1-like motif that mediates adherence to TLR5+ epithelial cells, TLR5 activation, and downstream signaling in vitro. TLR5 expression is associated with H. pylori infection and gastric lesions in human biopsies. Using Tlr5-knockout and wild-type mice, we show that TLR5 is important for efficient control of H. pylori infection. Our results indicate that CagL, by activating TLR5, may modulate immune responses to H. pylori.

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Variations in Helicobacter pylori Lipopolysaccharide To Evade the Innate Immune Component Surfactant Protein D

Infection and Immunity ◽

10.1128/iai.73.11.7677-7686.2005 ◽

2005 ◽

Vol 73 (11) ◽

pp. 7677-7686 ◽

Cited By ~ 38

Author(s):

Wafa Khamri ◽

Anthony P. Moran ◽

Mulugeta L. Worku ◽

Q. Najma Karim ◽

Marjorie M. Walker ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Phase Variation ◽

Surfactant Protein ◽

Clinical Isolates ◽

Surfactant Protein D ◽

Human Gastric Mucosa ◽

H Pylori

ABSTRACT Helicobacter pylori is a common and persistent human pathogen of the gastric mucosa. Surfactant protein D (SP-D), a component of innate immunity, is expressed in the human gastric mucosa and is capable of aggregating H. pylori. Wide variation in the SP-D binding affinity to H. pylori has been observed in clinical isolates and laboratory-adapted strains. The aim of this study was to reveal potential mechanisms responsible for evading SP-D binding and establishing persistent infection. An escape variant, J178V, was generated in vitro, and the lipopolysaccharide (LPS) structure of the variant was compared to that of the parental strain, J178. The genetic basis for structural variation was explored by sequencing LPS biosynthesis genes. SP-D binding to clinical isolates was demonstrated by fluorescence-activated cell sorter analyses. Here, we show that H. pylori evades SP-D binding through phase variation in lipopolysaccharide. This phenomenon is linked to changes in the fucosylation of the O chain, which was concomitant with slipped-strand mispairing in a poly(C) tract of the fucosyltransferase A (fucT1) gene. SP-D binding organisms are predominant in mucus in vivo (P = 0.02), suggesting that SP-D facilitates physical elimination. Phase variation to evade SP-D contributes to the persistence of this common gastric pathogen.

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Analysis of the microbial ecology between Helicobacter pylori and the gastric microbiota of Mongolian gerbils

Journal of Medical Microbiology ◽

10.1099/jmm.0.061135-0 ◽

2014 ◽

Vol 63 (1) ◽

pp. 129-137 ◽

Cited By ~ 14

Author(s):

Cynthia Zaman ◽

Takako Osaki ◽

Tomoko Hanawa ◽

Hideo Yonezawa ◽

Satoshi Kurata ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Microbial Ecology ◽

Inhibitory Effect ◽

Mongolian Gerbils ◽

Group 2 ◽

H Pylori ◽

Gastric Microbiota ◽

Group 1

Animal models are essential for in vivo analysis of Helicobacter-related diseases. Mongolian gerbils are used frequently to study Helicobacter pylori-induced gastritis and its consequences. The presence of some gastric microbiota with a suppressive effect on H. pylori suggests inhibitory gastric bacteria against H. pylori infection. The aim of the present study was to analyse the microbial ecology between H. pylori and the gastric microbiota of Mongolian gerbils. Gastric mucosa samples of H. pylori-negative and -positive gerbils were orally inoculated to five (Group 1) and six (Group 2) gerbils, respectively, and the gerbils were challenged with H. pylori infection. The colonization rate (40 %) of H. pylori in Group 1 gerbils was lower than the rate (67 %) in Group 2 gerbils. Culture filtrate of the gastric mucosa samples of Group 1 gerbils inhibited the in vitro growth of H. pylori. Three lactobacilli species, Lactobacillus reuteri, Lactobacillus johnsonii and Lactobacillus murinus, were isolated by anaerobic culture from the gerbils in Groups 1 and 2, and identified by genomic sequencing. It was demonstrated that the three different strains of lactobacilli exhibited an inhibitory effect on the in vitro growth of H. pylori. The results suggested that lactobacilli are the dominant gastric microbiota of Mongolian gerbils and the three lactobacilli isolated from the gastric mucosa samples with an inhibitory effect on H. pylori might have an anti-infective effect against H. pylori.

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The Role of E-cadherin in Helicobacter pylori-Related Gastric Diseases

Current Drug Metabolism ◽

10.2174/1389200219666180625113010 ◽

2019 ◽

Vol 20 (1) ◽

pp. 23-28

Author(s):

Yunzhan Zhang ◽

Danyan Li ◽

Yunkai Dai ◽

Ruliu Li ◽

Yong Gao ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Precancerous Lesions ◽

Research Literature ◽

Gastric Diseases ◽

H Pylori ◽

The Relationship ◽

E Cadherin

Background: Helicobacter pylori (H. pylori)-related gastric diseases are a series of gastric mucosal disorders associated with H. pylori infection. Gastric cancer (GC) is widely believed to evolve from gastritis and gastric ulcer. As an important adhesion molecule of epithelial cells, E-cadherin plays a key role in the development of gastric diseases. In this review, we aim to seek the characteristic of E-cadherin expression at different stages of gastric diseases. Methods: We searched plenty of databases for research literature about E-cadherin expression in H. pylori-related gastric diseases, and reviewed the relationship of E-cadherin and H. pylori, and the role of E-cadherin at different stages of gastric diseases. Results: H. pylori was shown to decrease E-cadherin expression by various ways in vitro, while most of clinical studies have not found the relationship between H. pylori and E-cadherin expression. It is defined that poor outcome of GC is related to loss expression of E-cadherin, but it is still unclear when qualitative change of E-cadherin expression in gastric mucosa emerges. Conclusion: Expression level of E-cadherin in gastric cells may be a consequence of injury factors and body’s selfrepairing ability. More studies on E-cadherin expression in gastric mucosa with precancerous lesions need to be performed, which may be potential and useful for early detection, prevention and treatment of GC.

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Helicobacter pylori-Induced Activation of Human Endothelial Cells

Infection and Immunity ◽

10.1128/iai.70.8.4581-4590.2002 ◽

2002 ◽

Vol 70 (8) ◽

pp. 4581-4590 ◽

Cited By ~ 58

Author(s):

M. Innocenti ◽

A.-C. Thoreson ◽

R. L. Ferrero ◽

E. Strömberg ◽

I. Bölin ◽

...

Keyword(s):

Endothelial Cells ◽

Helicobacter Pylori ◽

Gastric Mucosa ◽

Adhesion Molecule ◽

Cell Activation ◽

Ulcer Formation ◽

Blood Group Antigens ◽

Adhesion Molecule Expression ◽

Human Endothelial Cells ◽

H Pylori

ABSTRACT Helicobacter pylori infection causes active chronic inflammation with a continuous recruitment of neutrophils to the inflamed gastric mucosa. To evaluate the role of endothelial cells in this process, we have examined adhesion molecule expression and chemokine and cytokine production from human umbilical vein endothelial cells stimulated with well-characterized H. pylori strains as well as purified proteins. Our results indicate that endothelial cells actively contribute to neutrophil recruitment, since stimulation with H. pylori bacteria induced upregulation of the adhesion molecules VCAM-1, ICAM-1, and E-selectin as well as the chemokines interleukin 8 (IL-8) and growth-related oncogene alpha (GRO-α) and the cytokine IL-6. However, there were large variations in the ability of the different H. pylori strains to stimulate endothelial cells. These interstrain variations were seen irrespective of whether the strains had been isolated from patients with duodenal ulcer disease or asymptomatic carriers and were not solely related to the expression of known virulence factors, such as the cytotoxin-associated gene pathogenicity island, vacuolating toxin A, and Lewis blood group antigens. In addition, one or several unidentified proteins which act via NF-κB activation seem to induce endothelial cell activation. In conclusion, human endothelial cells produce neutrophil-recruiting factors and show increased adhesion molecule expression after stimulation with certain H. pylori strains. These effects probably contribute to the continuous recruitment of neutrophils to H. pylori-infected gastric mucosa and may also contribute to tissue damage and ulcer formation.

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Potential Association of EEF1A Dimethylation at Lysine 55 in the Basal Area of Helicobacter Pylori-Eradicated Gastric Mucosa with the Risk of Gastric Cancer: A Retrospective Observational Study

10.21203/rs.3.rs-1072695/v1 ◽

2021 ◽

Author(s):

Yuka Hirashita ◽

Masahide Fukuda ◽

Masaaki Kodama ◽

Yoshiyuki Tsukamoto ◽

Tadayoshi Okimoto ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Gastric Mucosa ◽

Eradication Therapy ◽

Basal Area ◽

Immunofluorescent Staining ◽

Upper Gastrointestinal Endoscopy ◽

H Pylori ◽

The Relationship

Abstract Background Although eradication therapy for chronic Helicobacter pylori reduces the risk of gastric cancer (GC), its effectiveness is incomplete. Therefore, it is critically important to identify those patients who remain at high risk after H. pylori eradication therapy. Accumulation of protein methylation is strongly implicated in cancer, and a recent study showed that dimethylation of eEF1A lysine 55 (eEF1AK55me2) promotes carcinogenesis in vivo. We aimed to investigate the relationship between eEF1A dimethylation and H. pylori status in gastric mucosa and to reveal potential downstream molecules of eEF1A dimethylation in H. pylori-eradicated mucosa. Methods Records of 115 patients (11 H. pylori-negative, 29 H. pylori-positive, 75 post-eradication patients) who underwent upper gastrointestinal endoscopy were retrospectively reviewed. The eEF1A dimethyl level was evaluated in each functional cell type of gastric mucosa by immunofluorescent staining. We also investigated the relationship between eEF1AK55me2 downregulation by CRISPR/Cas9-mediated deletion of Mettl13, which is known as a dimethyltransferase of eEF1AK55me2. Results The level of eEF1A dimethylation significantly increased in the surface and basal areas of H. pylori-positive mucosa compared with -negative mucosa (surface, p=0.0031; basal, p<0.0001). The eEF1A dimethyl levels in the surface area were significantly reduced by eradication therapy (p=0.005), but those in the basal area were maintained even after eradication therapy. Multivariate analysis revealed that high dimethylation of eEF1A in the basal area of the mucosa was the independent factor related to GC incidence (odds ratio=3.6611, 95% confidence interval=1.0350–12.949, p=0.0441). We also showed the relationship between eEF1A dimethylation and expressions of reprogramming factors Oct4 and Nanog by immunohistochemistry and in vitro genome editing experiments. Conclusions The results indicated that H. pylori infection potently induced eEF1A dimethylation in gastric mucosa. The accumulation of dimethyl-eEF1A in the basal area of the mucosa might contribute to GC risk via regulation of reprograming factors in H. pylori-eradicated gastric mucosa.

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Helicobacter pylori Pore-Forming Cytolysin Orthologue TlyA Possesses In Vitro Hemolytic Activity and Has a Role in Colonization of the Gastric Mucosa

Infection and Immunity ◽

10.1128/iai.69.3.1697-1703.2001 ◽

2001 ◽

Vol 69 (3) ◽

pp. 1697-1703 ◽

Cited By ~ 32

Author(s):

M. Celeste Martino ◽

Richard A. Stabler ◽

Zun W. Zhang ◽

Michael J. G. Farthing ◽

Brendan W. Wren ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Hemolytic Activity ◽

Wild Type Strain ◽

Bacterial Species ◽

Adenocarcinoma Cells ◽

Human Gastric Adenocarcinoma ◽

H Pylori

ABSTRACT Hemolysins have been found to possess a variety of functions in bacteria, including a role in virulence. Helicobacter pylori demonstrates hemolytic activity when cultured on unlysed blood agar plates which is increased under iron-limiting conditions. However, the role of an H. pylori hemolysin in virulence is unclear. Scrutiny of the H. pylori 26695 genome sequence suggests the presence of at least two distinct hemolysins, HP1086 and HP1490, in this strain. Previous studies have shown that the in vitro hemolytic activity of H. pylori is reduced when it is coincubated with dextran 5000, suggesting the presence of a pore-forming cytolysin. HP1086 has homology to pore-forming cytolysins (TlyA) from other bacterial species, and the introduction of the clonedH. pylori tlyA gene into a nonhemolyticEscherichia coli strain conferred hemolytic activity. AnH. pylori tlyA defined mutant showed reduced in vitro hemolytic activity, which appears to be due to pore formation, as the hemolytic activity of the wild-type strain is reduced to the same level as the tlyA mutant by the addition of dextran 5000. The mutant also showed reduced adhesion to human gastric adenocarcinoma cells and failed to colonize the gastric mucosa of mice. These data clearly suggest a role in virulence for H. pyloriTlyA, contrary to the suggestion that hemolytic activity is an in vitro phenomenon for this pathogen.

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Gastric Helicobacters in Domestic Animals and Nonhuman Primates and Their Significance for Human Health

Clinical Microbiology Reviews ◽

10.1128/cmr.00041-08 ◽

2009 ◽

Vol 22 (2) ◽

pp. 202-223 ◽

Cited By ~ 172

Author(s):

Freddy Haesebrouck ◽

Frank Pasmans ◽

Bram Flahou ◽

Koen Chiers ◽

Margo Baele ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Lymphoid Tissue ◽

Direct Contact ◽

Nonhuman Primates ◽

Domestic Animals ◽

Human Stomach ◽

Gastric Ulcers ◽

H Pylori

SUMMARY Helicobacters other than Helicobacter pylori have been associated with gastritis, gastric ulcers, and gastric mucosa-associated lymphoid tissue lymphoma in humans. These very fastidious microorganisms with a typical large spiral-shaped morphology were provisionally designated “H. heilmannii,” but in fact they comprise at least five different Helicobacter species, all of which are known to colonize the gastric mucosa of animals. H. suis, which has been isolated from the stomachs of pigs, is the most prevalent gastric non-H. pylori Helicobacter species in humans. Other gastric non-H. pylori helicobacters colonizing the human stomach are H. felis, H. salomonis, H. bizzozeronii, and the still-uncultivable “Candidatus Helicobacter heilmannii.” These microorganisms are often detected in the stomachs of dogs and cats. “Candidatus Helicobacter bovis” is highly prevalent in the abomasums of cattle but has only occasionally been detected in the stomachs of humans. There are clear indications that gastric non-H. pylori Helicobacter infections in humans originate from animals, and it is likely that transmission to humans occurs through direct contact. Little is known about the virulence factors of these microorganisms. The recent successes with in vitro isolation of non-H. pylori helicobacters from domestic animals open new perspectives for studying these microorganisms and their interactions with the host.

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In VivoExpression of Helicobacter pylori Virulence Genes in Patients with Gastritis, Ulcer, and Gastric Cancer

Infection and Immunity ◽

10.1128/iai.05845-11 ◽

2011 ◽

Vol 80 (2) ◽

pp. 594-601 ◽

Cited By ~ 12

Author(s):

Francisco Avilés-Jiménez ◽

Adriana Reyes-Leon ◽

Erik Nieto-Patlán ◽

Lori M. Hansen ◽

Juan Burgueño ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Environmental Conditions ◽

Virulence Genes ◽

Content Type ◽

Ulcer Disease ◽

Type Iv ◽

H Pylori

ABSTRACTThe best-studiedHelicobacter pylorivirulence factor associated with development of peptic ulcer disease or gastric cancer (GC) rather than asymptomatic nonatrophic gastritis (NAG) is thecagpathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into host epithelial cells. Here we used real-time reverse transcription-PCR (RT-PCR) to measure thein vivoexpression of genes on thecagPAI and of other virulence genes in patients with NAG, duodenal ulcer (DU), or GC.In vivoexpression ofH. pylorivirulence genes was greater overall in gastric biopsy specimens of patients with GC than in those of patients with NAG or DU. However, sincein vitroexpression ofcagAwas not greater inH. pyloristrains from patients with GC than in those from patients with NAG or DU, increased expression in GCin vivois likely a result of environmental conditions in the gastric mucosa, though it may in turn cause more severe pathology. Increased expression of virulence genes in GC may represent a stress response to elevated pH or other environmental conditions in the stomach of patients with GC, which may be less hospitable toH. pyloricolonization than the acidic environment in patients with NAG or DU.

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