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Background: Despite extensive experimental investigation stressing the importance of bacterial interaction with dendritic cells (DCs), evidence regarding direct interaction of Helicobacter pylori or its virulence products with DCs in the human gastric mucosa is lacking., Methods: Human gastric mucosa biopsies, with or without H. pylori infection and active inflammation, were investigated at light and electron microscopy level with immunocytochemical tests for bacterial products (VacA, urease, outer membrane proteins) and DC markers (DC-SIGN, CD11c, CD83) or with the DC-labeling ZnI(2)-OsO(4 )technique. Parallel tests with cultured DCs were carried out., Results: Cells reproducing ultrastructural and cytochemical patterns of DCs were detected in the lamina propria and epithelium of heavily infected and inflamed (but not of normal) mucosa, where DC luminal endings directly contact H. pylori and take up their virulence products. Cytotoxic changes (mitochondrial swelling, cytoplasmic vacuolation, autophagy) were observed in intraepithelial DCs and reproduced in cultured DCs incubated with H. pylori broth culture filtrates to obtain intracellular accumulation of VacA and urease. Granulocytes were also seen to contact and heavily phagocytose luminal H. pylori, while macrophages remained confined to basal epithelium, though taking up bacteria and bacterial products., Conclusion: Human DCs can enter H. pylori-infected gastric epithelium, in association with other innate immunity cells, to take up bacteria and their virulence products. This process is likely to be important for bacterial sensing and pertinent immune response; however, it may also generate DC cytotoxic changes potentially hampering their function.

Background: Interactions between bacterial components and polymorphonuclear leukocytes (PMNL) play a major pathogenic role in Helicobacter pylori-associated diseases. Activation of PMNL can be induced by contact with whole bacteria or by different H. pylori products released in the extracellular space either by active secretion or by bacterial autolysis. Among these products, H. pylori VacA is a secreted toxin inducing vacuolation and apoptosis of epithelial cells., Methods and Results: We found that non-opsonic human PMNL were sensitive to the vacuolating effect of VacA+ broth culture filtrate (BCF) and of purified VacA toxin. PMNL incubated with VacA+ BCF showed Rab7-positive large intracytoplasmic vacuoles. PMNL preincubation with H. pylori BCF of different phenotypes dramatically potentialized the oxidative burst induced by zymosan, increased phagocytosis of opsonized fluorescent beads, and up-regulated CD11b cell surface expression, but independently of the BCF VacA phenotype. Moreover, by using purified VacA toxin we showed that vacuolation induced in PMNL did not modify the rate of spontaneous PMNL apoptosis measured by caspase 3 activity., Conclusions: Taken together, these data showed that human PMNL is a sensitive cell population to H. pylori VacA toxin. However, activation of PMNL (i.e., oxidative burst, phagocytosis, CD11b up-regulation) and PMNL apoptosis are not affected by VacA, raising question about the role of VacA toxin on PMNL in vivo.

Helicobacter pylori (H. pylori) is a highly successful human pathogen that colonizes stomach in around 50% of the global population. The colonization of bacterium induces an inflammatory response and a substantial rise in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), mostly derived from host neutrophils and gastric epithelial cells, which play a crucial role in combating bacterial infections. However, H. pylori has developed various strategies to quench the deleterious effects of ROS, including the production of antioxidant enzymes, antioxidant proteins as well as blocking the generation of oxidants. The host's inability to eliminate H. pylori infection results in persistent ROS production. Notably, excessive ROS can disrupt the intracellular signal transduction and biological processes of the host, incurring chronic inflammation and cellular damage, such as DNA damage, lipid peroxidation, and protein oxidation. Markedly, the sustained inflammatory response and oxidative stress during H. pylori infection are major risk factor for gastric carcinogenesis. In this context, we summarize the literature on H. pylori infection‐induced ROS production, the strategies used by H. pylori to counteract the host response, and subsequent host damage and gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: Cancer immunotherapy has shown promising results in several tumors, but its efficacy is influenced by the immune state of the body. Helicobacter pylori (H. pylori) infection can modulate the immune function of the body through various pathways, ultimately affecting the effectiveness of cancer immunotherapy. Aim: In this meta‐analysis, we aimed to explore the association between H. pylori infection and the efficacy of cancer immunotherapy. Methods: We conducted a comprehensive search of PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials to identify relevant articles. We extracted and pooled the hazard ratio (HR) of the overall survival (OS) and progression‐free survival (PFS) by Review Manager 5.4. Results: Our analysis included four studies with a total of 263 participants. Compared to the control group, patients receiving cancer immunotherapy with H. pylori infection had a shorter OS (HR = 2.68, 95% CI: 2.00–4.11, p < 0.00001) and PFS (HR = 2.25, 95% CI: 1.66–3.60, p < 0.00001). Conclusion: Our meta‐analysis suggested that H. pylori infection has a detrimental effect on cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Chronic atrophic gastritis (CAG) is a pathological stage in the Correa's cascade, whereby Helicobacter pylori (H. pylori) infection is the primary cause. Cellular senescence is an inducing factor for cancer occurrence and cellular senescence is an obvious phenomenon in gastric mucosal tissues of H. pylori‐positive CAG patients. Methods: In this review, we collated the information on cellular senescence and H. pylori‐positive CAG. Results: At present, only a few studies have observed the effect of cellular senescence on precancerous lesions. In combination with the latest research, this review has collated the information on cellular senescence and H. pylori‐positive CAG from four aspects‐ telomere shortening, DNA methylation, increased reacive oxygen species (ROS) production, and failure of autophagy. Conclusion: This is expected to be helpful for exploring the relevant mechanisms underlying inflammatory cancerous transformation and formulating appropriate treatment strategies. [ABSTRACT FROM AUTHOR]

Even though Helicobacter pylori infection was the most causative factor of gastric cancer, numerous in vivo studies failed to induce gastric cancer using H. pylori infection only. The utilization of established animal studies in cancer research is crucial as they aim to investigate the coincidental association between suspected oncogenes and pathogenesis as well as generate models for the development and testing of potential treatments. The methods to establish gastric cancer using infected animal models remain limited, diverse in methods, and showed different results. This study investigates the differences in animal models, which highlight different pathological results in gaster by literature research. Electronic databases searched were performed in PubMed, Science Direct, and Cochrane, without a period filter. A total of 135 articles were used in this study after a full‐text assessment was conducted. The most frequent animal models used for gastric cancer were Mice, while Mongolian gerbils and Transgenic mice were the most susceptible model for gastric cancer associated with H. pylori infection. Additionally, transgenic mice showed that the susceptibility to gastric cancer progression was due to genetic and epigenetic factors. These studies showed that in Mongolian gerbil models, H. pylori could function as a single agent to trigger stomach cancer. However, most gastric cancer susceptibilities were not solely relying on H. pylori infection, and numerous factors are involved in cancer progression. Further study using Mongolian gerbils and Transgenic mice is crucial to conduct and establish the best models for gastric cancer associated H. pylori. [ABSTRACT FROM AUTHOR]

Background: The role of H. pylori infection has been reported in various extragastric diseases, particularly, the correlation between H. pylori and atherosclerosis (AS) have received lots of attention. Some scholars demonstrated that the presence of H. pylori‐specific DNA in the sclerotic plaques of atheromatous patients provides biological evidences, with indicating that H. pylori infection is a potential factor of AS. However, the underlying mechanism of H. pylori or their products cross the epithelial barriers to enter the blood circulation remains unclear. Recent studies have shown that the extracellular vesicles (EVs) derived from H. pylori‐infected gastric epithelial cells encapsulated H. pylori virulence factor cytotoxin‐associated gene A (CagA) and existed in the blood samples of patients or mice, which indicating that they can carry CagA into the blood circulation. Based on these findings, some researchers proposed a hypothesis that H. pylori is involved in the pathogenesis of AS via EVs‐based mechanisms. In addition, outer membrane vesicles (OMVs) serve as transport vehicles to deliver H. pylori virulence factors to epithelial cells. It is necessary to discuss the role of H. pylori OMVs in the development of AS. Objectives: This review will focus on the correlation between H. pylori infection and AS and tried to unveil the possible role of EVs from H. pylori‐infected cells and H. pylori OMVs in the pathogenesis of AS, with a view to providing help in refining our knowledge in this aspect. Methods: All of information included in this review was retrieved from published studies on H. pylori infection in AS. Results: H. pylori infection may be an atherosclerotic risk factor and drives researchers to reevaluate the role of H. pylori in the pathogenesis of AS. Some findings proposed a new hypothesis that H. pylori may be involved in the pathogenesis of AS through EVs‐based mechanisms. Besides EVs from H. pylori‐infected cells, whether H. pylori OMVs may play some role in the pathogenesis of AS is still remain unclear. Conclusion: Existing epidemiological and clinical evidence had shown that there is a possible association between H. pylori and AS. However, except for the larger randomized controlled trials, more basic research about EVs from H. pylori‐infected cells and H. pylori OMVs is the need of the hour to unveil the possible role of H. pylori infection in the pathogenesis of AS. [ABSTRACT FROM AUTHOR]

Presents abstracts on the virulence factors and pathogenesis of Helicobacter pylori infection. "The Helicobacter Pylori CagA Protein Requires Both N-Terminal and C-Terminal Signals for Type IV Secretion," by S. Hohlfeld, R. Haas, W. Fischer; "Role of Outer Membrane Proteins in Adherence of Helicobacter Pylori to Gastric Cells," by K. Engel, R. Haad, S. Odenbreit; "Induction of Activation and Maturation of Human Dendritic Cells by H. Pylori," by W. Schneider-Brachert, N. Lehn and K. Kranzer; "VacA Release by H. Pylori: Quantitation and Vacuolating Activity of Free-Solubel and Outer Membrane Vesicle-Associated Toxin," by V. Ricci, V. Necchi and U. Ventura; Others.

Background: Bismuth quadruple (BQT) and non‐bismuth quadruple (N‐BQT) therapies are the recommended first‐line treatments for Helicobacter (H.) pylori infection. Objective: To compare the efficacy of BQT and N‐BQT in clinical practice in an area with high clarithromycin resistance, choosing the regimen on the basis of previous exposure to clarithromycin. Methods: A total of 404 consecutive H pylori‐positive, naïve patients were enrolled. A total of 203 patients without previous exposure to clarithromycin received N‐BQT, 100 patients for 10 days and 103 for 14 days, whereas 201 with previous exposure to clarithromycin received 10‐day BQT. Efficacy and treatment‐related adverse events were assessed. Results and Conclusions: Eradication rates by intention‐to‐treat analysis were 88.2% for N‐BQT and 91.5% for BQT (P =.26); per‐protocol analysis eradication rates were 91.2% and 95.8% for N‐BQT and BQT, respectively (P =.07). Eradication rates were significantly higher with 14‐day than 10‐day CT (P <.003). Almost all patients had a good compliance with both N‐BQT (95.6%) and BQT (95%). Adverse events occurred in 24.1% and 26.9% (P =.53) of patients in the N‐BQT and BQT group, respectively. In conclusion, clarithromycin‐containing non‐bismuth or bismuth quadruple therapy, based on the knowledge of previous clarithromycin exposure, is effective and safe even in an area of high prevalence of clarithromycin‐resistant H pylori strains. [ABSTRACT FROM AUTHOR]

Background Gastritis, ulcers, and gastric malignancy have been linked to human gastric epithelial colonization by Helicobacter pylori. Characterization of the mechanisms by which H. pylori adapts to the human stomach environment is of crucial importance to understand H. pylori pathogenesis. Material and Methods In an effort to extend our knowledge of these mechanisms, we used proteomic analysis and qRT- PCR to characterize the role of the histone-like protein HU in the response of H. pylori to low pH. Results Proteomic analysis revealed that genes involved in chemotaxis, oxidative stress, or metabolism are under control of the HU protein. Also, expression of the virulence factors Ggt and NapA is affected by the null mutation of hup gene both at neutral and acid pH, as evidenced by qRT- PCR analysis. Conclusions Those results showed that H. pylori gene expression is altered by shift to low pH, thus confirming that acid exposure leads to profound changes in genomic expression, and suggest that the HU protein is a regulator that may help the bacterium adapt to the acid stress. In accordance with previous reports, we found that the HU protein participates in gene expression regulation when the microorganism is exposed to acid stress. Such transcriptional regulation underlies protein accumulation in the H. pylori cell. [ABSTRACT FROM AUTHOR]

Background Spices have been used for thousands of years, and recent studies suggest that certain spices confer beneficial effects on gastric disorders. The purpose of this study was to evaluate possible chemopreventive effects of spice-derived compounds on Helicobacter pylori ( H. pylori)-induced gastritis. Methods We examined the inhibitory effects of curcumin, capsaicin, and piperine on H. pylori in vitro by determining the colony-forming units and real-time RT- PCR in H. pylori stimulated AGS gastric cancer cells. For in vivo analysis, 6-week-old SPF male Mongolian gerbils were infected with H. pylori, fed diets containing 5000 ppm curcumin, 100 ppm capsaicin, or 100 ppm piperine, and sacrificed after 13 weeks. Results All three compounds inhibited in vitro proliferation of H. pylori, with curcumin being the most effective. Infiltration of neutrophils and mononuclear cells was suppressed by piperine both in the antrum and corpus of H. pylori-infected gerbils. Capsaicin also decreased neutrophils in the antrum and corpus and mononuclear cell infiltration and heterotopic proliferative glands in the corpus. m RNA expression of Tnf-α and formation of phospho- Iκ B-α in the antrum were reduced by both capsaicin and piperine. In addition, piperine suppressed expression of Il- 1β, Ifn-γ, Il-6, and i Nos, while H. pylori Ure A and other virulence factors were not significantly attenuated by any compounds. Conclusion These results suggest that capsaicin and piperine have anti-inflammatory effects on H. pylori-induced gastritis in gerbils independent of direct antibacterial effects and may thus have potential for use in the chemoprevention of H. pylori-associated gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Background and aim Adherence to the gastric epithelium is one of the most important steps of Helicobacter pylori to remain and cause disease. The aim of this study was to analyze whether H. pylori isolates from patients with different gastroduodenal diseases present differences in the pattern of adherence to gastric epithelial cells ( AGS), in the ability to induce IL-8, and in the presence of virulence genes. Methods We tested 75 H. pylori strains isolated from nonatrophic gastritis, gastric cancer, and duodenal ulcer patients. The adhesion pattern and IL-8 induction were determined in AGS cells, and invasion of AGS cells was studied using a gentamicin protection assay. The IL-8 levels induced were determined by ELISA. Results Helicobacter pylori strains presented diffuse adherence ( DA) and localized ( LA) adherence patterns, similar to those described for enteropathogenic E. coli ( EPEC), were observed in AGS cells. A DA pattern was observed in 57% and LA in 43% of the strains, and DA was more frequent in isolates from patients with gastric cancer ( p = 0.044). Strains with a LA pattern induced higher levels of IL-8 ( p = 0.042) in AGS cells. Conclusion The adherence pattern was not associated with neither invasiveness nor with the presence of virulence genes. Our study shows that H. pylori strains present adherence patterns to AGS cells resembling those observed in EPEC and that these patterns may be associated with disease and with activity on AGS cells. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori (H. pylori) are resistant to hostile gastric environments and antibiotic therapy, reflecting the possibility that they are protected by an ecological niche, such as inside the vacuoles of human epithelial and immune cells. Acanthamoeba castellanii may also provide such an alternative niche, as fluorescently labeled H. pylori were observed as fast-moving and viable bacterium-like bodies inside the vacuoles of gastric, oral-fecal and water--food-borne Acanthamoeba castellanii. In addition, H. pylori-specific genes and proteins were detected in samples extracted from these ameba cells. The coccoid forms of H. pylori present within this ameba are converted to spiral form and produce peroxiredoxin and thiol peroxidase, providing the ability to detoxify oxygen metabolites formed in immune cells. Furthermore, these bacteria produce urease and vacA, two virulence determinants of H. pylori that influence phago-lysosome fusion and bacterial survival in macrophages. Microscopic observations of H. pylori cells in new generations of ameba along with amplification of H. pylori-specific genes from consecutive generations indicate that new ameba can inherit the intracellular H. pylori as part of their vacuolar content. Accordingly, it is proposed that Acanthamoeba vacuoles serve as sophisticated niche that protects H. pylori against the environmental stresses and provides essential nutrients for its growth and multiplication. This intracellular establishment inside the Acanthamoeba vacuole likely occurred long ago, leading to the adaptation of H. pylori to persist in phagocytic cells. The presence of these bacteria within Acanthamoeba, along with the transmission of Acanthamoeba from sewage, saliva water to others, provides explanations for the persistence and propagation of H. pylori in the human population. Objective: This topic highlights the reviews and discusses recent evidence regarding the evolutionary adaptation of H. pylori to thrive in host cell vacuoles. Method and Results: Helicobacter pylori (H. pylori) have been observed within Acanthamoeba vacuoles by light and fluorescence microscopy, and their presence has been confirmed by the detection of H. pylori-specific genes and proteins in Acanthamoeba extracts, such as vacA subunits, ureA, peroxiredoxin, and thiol peroxidase. Moreover, nonculturable H. pylori cells have been found in subsequent generations of Acanthamoeba, indicating the generational transmission of the bacteria as part of the transfer of vacuolar content. Conclusion: H.pylori are therefore well equipped to establish in the vacuoles of Acanthamoeba, which provide them with essential nutrients for multiplication, as a pre-adaptation for invasion of human cells. Due to general tropism of all bacteria to yeast extract, entrance of H. pylori into candida was modified by our experiments and it is corrected to "Acanthamoeba". [ABSTRACT FROM AUTHOR]

Background: Epithelial junctions and mucins compose a major portion of the mucosal barrier. Helicobacter pylori (H. pylori) infections induce alterations of the tight junctions and adherens junctions in epithelial cells, although the precise mechanisms underlying this process are not fully understood. Methods: The expression of adhesion molecules and MUC1 was systematically investigated in gastrointestinal epithelial cells infected with H. pylori in vitro and in vivo. Furthermore, we developed several new in vitro methods to study the relationships between the bacterium and the dysfunction of tight junctions using Boyden Chambers. Results: The expression of a series of junctional molecules and MUC1 decreased in the cultured cells that were infected with H. pylori. According to the degree of damage at the tight junctions, direct contact of H. pylori with the apical membrane of the cells resulted in the greatest increase in permeability compared to basal membrane binding or non-binding of H. pylori to the cells. Similarly, we noted that H. pylori infection could reduce the expression and glycosylation of MUC1. Conclusions: Helicobacter pylori dwelling on the apical surface of the gastrointestinal epithelium could directly induce serious injury of the mucosal barrier, and the new methods outlined here, based on the Boyden Chamber system, could be very useful for studying the relationships between bacteria and their target cells. [ABSTRACT FROM AUTHOR]

Background The envisaged roles and partly understood functional properties of Helicobacter pylori protein HP0986 are significant in the context of proinflammatory and or proapoptotic activities, the two important facilitators of pathogen survival and persistence. In addition, sequence analysis of this gene predicts a restriction endonuclease function which remained unknown thus far. To evaluate the role of HP0986 in gastric inflammation, we studied its expression profile using a large number of clinical isolates but a limited number of biopsies and patient sera. Also, we studied antigenic role of HP0986 in altering cytokine responses of human gastric epithelial ( AGS) cells including its interaction with and localization within the AGS cells. Materials and Methods For in vitro expression study of HP0986, 110 H. pylori clinical isolates were cultured from patients with functional dyspepsia. For expression analysis by q RT PCR of HP0986, 10 gastric biopsy specimens were studied. HP0986 was also used to detect antibodies in patient sera. AGS cells were incubated with recombinant HP0986 to determine cytokine response and NF-κB activation. Transient transfection with HP0986 cloned in pEGFPN1 was used to study its subcellular localization or homing in AGS cells. Results Out of 110 cultured H. pylori strains, 34 (31%) were positive for HP0986 and this observation was correlated with in vitro expression profiles. HP0986 mRNA was detected in 7 of the 10 biopsy specimens. Further, HP0986 induced IL-8 secretion in gastric epithelial cells in a dose and time-dependent manner via NF-κB pathway. Serum antibodies against HP0986 were positively associated with H. pylori positive patients. Transient transfection of AGS cells revealed both cytoplasmic and nuclear localization of HP0986. Conclusion HP0986 was moderately prevalent in clinical isolates and its expression profile in cultures and gastric biopsies points to its being naturally expressed. Collective observations including the induction of IL-8 via TNFR1 and NF-κB, subcellular localization, and seropositivity data point to a significant role of HP0986 in gastroduodenal inflammation. We propose to name the HP0986 gene/protein as 'TNFR1 interacting endonuclease A (TieA or tieA)'. [ABSTRACT FROM AUTHOR]

Background Helicobacter pylori ( Hp)-related gastritis is characterized by a predominant T helper ( Th)1/ Th17 cell immunity. Ghrelin ( GR) has immunoregulatory properties and inhibits experimental Th cell-dependent pathology. Aims To evaluate whether Hp infection associates with changes in GR expression and whether GR negatively regulates Th1/ Th17 cytokines during Hp infection. Methods GR expression was evaluated by real-time PCR in gastric biopsies taken from Hp-infected and Hp-uninfected patients and in gastric biopsies of Hp-negative subjects cultured with or without H. pylori culture supernatant. To examine whether GR regulates Hp-induced cytokine production, H. pylori-infected gastric biopsies were stimulated with GR, and interleukin ( IL)-12, interferon ( IFN)-γ and IL-4 transcripts were evaluated by real-time PCR. IL-12 and IFN-γ were also analyzed in lamina propria mononuclear cells ( LPMCs) extracted from Hp-infected gastric biopsies and cultured with GR. Results GR RNA transcripts were reduced in biopsies from Hp-infected patients. Treatment of Hp-negative gastric biopsies with Hp culture supernatant reduced GR RNA expression. GR dose-dependently inhibited RNA expression of IL-12 and IFN-γ but not IL-4 in ex vivo cultures of mucosal explants and in cultures of gastric LPMCs from Hp-positive patients. Conclusions GR is downregulated in the gastric mucosa of H. pylori-infected patients. Such a defect could contribute to sustain the ongoing Th1-cell response. [ABSTRACT FROM AUTHOR]

Background and Aims: Helicobacter pylori is a highly diverse pathogen, which encounters epithelial cells as the initial defense barrier during its lifelong infection. The structure of epithelial cells can be disrupted through cleavage of microfilaments. Cytokeratin 18 (CK18) is an intermediate filament, the cleavage of which is considered an early event during apoptosis following activation of effector caspases. Methods: Helicobacter pylori strains were isolated from 76 dyspeptic patients. cagA 3' variable region and CagA protein status were analyzed by PCR and western blotting, respectively. Eight hours post-co-culture of AGS cells with different H. pylori strains, flow cytometric analysis was performed using M30 monoclonal antibody specific to CK18 cleavage-induced neo-epitope. Results: Higher rates of CK18 cleavage were detected during co-culture of AGS cells with H. pylori strains bearing greater numbers of cagA EPIYA-C and multimerization (CM) motifs. On the other hand, H. pylori strains with greater numbers of EPIYA-B relative to EPIYA-C demonstrated a decrease in CK18 cleavage rate. Thus, H. pylori-mediated cleavage of CK18 appeared proportional to the number of CagA EPIYA-C and CM motifs, which seemed to be downplayed in the presence of EPIYA-B motifs. Conclusions: Our observation associating the heterogeneity of cagA variants with the potential of H. pylori strains in the induction of CK18 cleavage as an early indication of apoptosis in gastric epithelial cells supports the fact that apoptosis may be a type-specific trait. However, additional cagA-targeted experiments are required to clearly identify the role of EPIYA and CM motifs in apoptosis and/or the responsible effector molecules. [ABSTRACT FROM AUTHOR]

An author index for the 2012 issue of "Helicobacter" is presented.

Helicobacter pylori infections and clinical outcome are dependent on sophisticated interactions between the bacteria and its host. Crucial bacterial factors associated with pathogenicity comprise a type IV secretion system encoded by the cag pathogenicity island, the effector protein CagA, the vacuolating cytotoxin (VacA), peptidoglycan, lipopolysaccharide (LPS), γ-glutamyl transpeptidase (GGT), protease HtrA, and the adhesins BabA, SabA, and others. The high number of these factors and allelic variation of the involved genes generates a highly complex scenario and reveals the difficulties in testing the contribution of each individual factor. Much effort has been put into identifying the molecular mechanisms associated with H. pylori-associated pathogenesis using human primary tissues, Mongolian gerbils, transgenic, knockout, and other mice as well as in vitro cell model systems. Interactions between bacterial factors and host signal transduction pathways seem to be critical for mediating the induction of pathogenic downstream processes and disease development. In this review article, we discuss the most recent progress in this research field. [ABSTRACT FROM AUTHOR]

Helicobacter pylori infection is regarded as the major cause of various gastric diseases and induces the production of several cytokines including interleukin-17 (IL-17) recently recognized as an important player in the mammalian immune system. This review deals with the role of IL-17 on the H. pylori-induced infection and immunity in humans and experimental animals. H. pylori infection increases IL-17 in the gastric mucosa of humans and experimental animals. In humans, IL-17 induces the secretion of IL-8 by activating the ERK 1/2 MAP kinase pathway and the released IL-8 attracts neutrophils promoting inflammation. IL-23 is increased in patients with H. pylori-related gastritis and regulates IL-17 secretion via STAT3 pathway. Studies in H. pylori-infected mice indicate that IL-17 is primarily associated with gastric inflammation. The early events in the immune response of immunized and challenged mice include the recruitment of T cells and the production of IL-17. Neutrophil attracting chemokines are released, and the bacterial load is considerably reduced. IL-17 plays a dual role in infection and vaccination. In infection, T regulatory cells (Tregs) suppress the inflammatory reaction driven by IL-17 thereby favoring bacterial persistence. Immunization produces Helicobacter-specific memory T-helper cells that can possibly alter the ratio between T-helper 17 and Treg responses so that the IL-17-driven inflammatory reaction can overcome the Treg response leading to bacterial clearance. IL-17 plays an important role in H. pylori-related gastritis and in the reduction of Helicobacter infection in mice following immunization. [ABSTRACT FROM AUTHOR]

Helicobacter pylori represents the major etiologic agent of gastritis, gastric, and duodenal ulcer disease and can cause gastric cancer and mucosa-associated lymphoid tissue B-cell lymphoma. It is clear that the consequences of infection reflect diverse outcomes of the interaction of bacteria and host immune system. The hope is that by deciphering the deterministic rules - if any - of this interplay, we will eventually be able to predict, treat, and ultimately prevent disease. Over the past year, research on the immunology of this infection started to probe the role of small noncoding RNAs, a novel class of immune response regulators. Furthermore, we learned new details on how infection is detected by innate pattern recognition receptors. Induction of effective cell-mediated immunity will be key for the development of a vaccine, and new work published analyzed the relevance and contribution of CD4 T helper cell subsets to the immune reaction. Th17 cells, which are also induced during natural infection, were shown to be particularly important for vaccination. Cost-efficiency of vaccination was re-assessed and confirmed. Thus, induction and shaping of the effector roles of such protective Th populations will be a target of the newly described vaccine antigens, formulations, and modes of application that we also review here. [ABSTRACT FROM AUTHOR]

Several bacterial pathogens inject virulence proteins into host target cells that are substrates of eukaryotic tyrosine kinases. One of the key examples is the Helicobacter pylori CagA effector protein which is translocated by a type-IV secretion system. Injected CagA becomes tyrosine-phosphorylated on EPIYA sequence motifs by Src and Abl family kinases. CagA then binds to and activates/inactivates multiple signaling proteins in a phosphorylation-dependent and phosphorylation-independent manner. A recent proteomic screen systematically identified eukaryotic binding partners of the EPIYA phosphorylation sites of CagA and similar sites in other bacterial effectors by high-resolution mass spectrometry. Individual phosphorylation sites recruited a surprisingly high number of interaction partners suggesting that each phosphorylation site can interfere with many downstream pathways. We now count 20 reported cellular binding partners of CagA, which represents the highest quantitiy among all yet known virulence-associated effector proteins in the microbial world. This complexity generates a highly remarkable and puzzling scenario. In addition, the first crystal structure of CagA provided us with new information on the function of this important virulence determinant. Here we review the recent advances in characterizing the multiple binding signaling activities of CagA. Injected CagA can act as a ‘master key’ that evolved the ability to highjack multiple host cell signalling cascades, which include the induction of membrane dynamics, actin-cytoskeletal rearrangements and the disruption of cell-to-cell junctions as well as proliferative, pro-inflammatory and anti-apoptotic nuclear responses. The discovery that different pathogens use this common strategy to subvert host cell functions suggests that more examples will emerge soon. [ABSTRACT FROM AUTHOR]

Background and Aim: Our previous study of Helicobacter pylori-induced apoptosis showed the involvement of Bcl-2 family proteins and cytochrome c release from mitochondria. Here, we examine the release of other factors from mitochondria, such as apoptosis-inducing factor (AIF), and upstream events involving caspase-8 and Bid. Methods: Human gastric adenocarcinoma (AGS) cells were incubated with a cagA-positive H. pylori strain for 0, 3, 6, and 24 hours and either total protein or cytoplasmic, nuclear, and mitochondrial membrane fractions were collected. Results: Proteins were immunoblotted for AIF, Bid, polyadenosine ribose polymerase (PARP), caspase-8, and β-catenin. H. pylori activated caspase-8, caused PARP cleavage, and attenuated mitochondrial membrane potential. A time-dependent decrease in β-catenin protein expression was detected in cytoplasmic and nuclear extracts, coupled with a decrease in β-actin. An increase in the cytoplasmic pool of AIF was seen as early as 3 hours after H. pylori exposure, and a concomitant increase was seen in nuclear AIF levels up to 6 hours. A band corresponding to full-length Bid was seen in both the cytoplasmic and the nuclear fractions of controls, but not after H. pylori exposure. Active AIF staining was markedly increased in gastric mucosa from infected persons, compared to uninfected controls. Conclusion: H. pylori might trigger apoptosis in AGS cells via interaction with death receptors in the plasma membrane, leading to the cleavage of procaspase-8, release of cytochrome c and AIF from mitochondria, and activation of subsequent downstream apoptotic events, as reported previously for chlorophyllin. This is consistent with AIF activation that was found in the gastric mucosa of humans infected with H. pylori. Hence, the balance between apoptosis and proliferation in these cells may be altered in response to injury caused by H. pylori infection, leading to an increased risk of cancer. [ABSTRACT FROM AUTHOR]

Background: Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in the destruction of the extracellular matrix and basement membrane. The induction of uPA and uPAR in the gastric cancer cells with H. pylori has been demonstrated previously. The involvement of COX-2-PGE2 pathway in the uPA system (uPA and uPAR) expression is unclear. Methods: Gastric cancer cells (MKN45) were co-cultured with H. pylori standard strain (NCTC11637). The specific inductions of uPA and uPAR mRNA were examined by reverse transcription-polymerase chain reaction amplification. The secreted uPA antigen was measured by ELISA. To evaluate the involvement of COX-2 and PGE2 pathway in H. pylori-induced uPA and uPAR expressions, we examined the effects of COX-2 inhibitor and PGE2 receptor antagonist on H. pylori-induced uPA and uPAR expression in the gastric cancer cells. Results: The expressions of both uPA and uPAR mRNAs in the gastric cancer cells increased obviously (12-fold and 3-fold, respectively) with H. pylori stimulation. The amount of uPA antigen into the culture medium increased dramatically with H. pylori stimulation. The COX-2 expression level in the gastric cancer cells increased remarkably with H. pylori stimulation. H. pylori-induced uPA and uPAR expression levels were suppressed with COX2 inhibitor treatment. The amount of PGE2 antigen into the culture medium increased dramatically 24 hours after H. pylori stimulation. The gastric cancer cells expressed EP2 and EP4 subtypes. EP2 receptor antagonist suppressed the H. pylori-induced uPA and uPAR expressions in the gastric cancer cells. Conclusions: Our results indicated that COX2-PGE2 pathway may be involved in H. pylori-associated uPA and uPAR induction, and that COX-2 inhibitor or EP2 receptor antagonist may inhibit angiogenesis and tumor invasion via suppression of the uPA system. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori infection leads to gastritis, peptic ulcer, and gastric cancer, in part due to epithelial damage following bacteria binding to the epithelium. Infection with cag pathogenicity island (PAI) bearing strains of H. pylori is associated with increased gastric inflammation and a higher incidence of gastroduodenal diseases. It is now known that various effector molecules are injected into host epithelial cells via a type IV secretion apparatus, resulting in cytoskeletal changes and chemokine secretion. Whether binding of bacteria and subsequent apoptosis of gastric epithelial cells are altered by cag PAI status was examined in this study. Methods: AGS, Kato III, and N87 human gastric epithelial cell lines were incubated with cag PAI-positive or cag PAI-negative strains of H. pylori in the presence or absence of clarithromycin. Binding was evaluated by flow cytometry and scanning electron microscopy. Apoptosis was assessed by detection of DNA degradation and ELISA detection of exposed histone residues. Results: cag PAI-negative strains bound to gastric epithelial cells to the same extent as cag PAI-positive strains. Both cag PAI-positive and cag PAI-negative strains induced apoptosis. However, cag PAI-positive strains induced higher levels of DNA degradation. Incubation with clarithromycin inactivated H. pylori but did not affect binding. However, pretreatment with clarithromycin decreased infection-induced apoptosis. Conclusions: cag PAI status did not affect binding of bacteria to gastric epithelial cells but cag PAI-positive H. pylori induced apoptosis more rapidly than cag PAI-negative mutant strains, suggesting that H. pylori binding and subsequent apoptosis are differentially regulated with regard to bacterial properties. [ABSTRACT FROM AUTHOR]

Although there are attempts to perform Helicobacter pylori diagnosis directly in vivo using magnification endoscopy, most articles on diagnosis this year concerned non-invasive tests and molecular methods. For urea breath tests, there are attempts to have a quicker and cheaper test and to evaluate its role in cases of premalignant lesions. For stool antigens tests, evaluation of kits using monoclonal antibodies was carried out. Molecular tests have been applied for typing and detection of resistant mutants. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that an impaired T-cell response against Helicobacter pylori plays a role in the pathogenesis of H. pylori-related diseases. Cyclooxygenase (COX) 2 has been shown to inhibit the production of T-helper (Th) 1 cytokines. This study aimed to ascertain whether COX-2 downregulates Th1 signaling pathway in human gastric mucosa colonized by H. pylori. Methods: COX-2 expression and prostaglandin E2 (PGE2) production were determined in total proteins extracted from freshly obtained gastric biopsies of H. pylori-infected and uninfected patients by Western blotting and enzyme-linked immunosorbent assay (ELISA). Phosphorylated (p)STAT4, pSTAT1, T-bet, and pSTAT6 expression and interleukin (IL)-12, interferon (IFN)-γ, and IL-4 production were also determined by Western blotting and ELISA, respectively, in total protein extracts from gastric biopsy cultures of H. pylori-infected patients treated without and with COX-2 inhibitor NS-398. Results: Enhanced expression of COX-2 and production of PGE2 was found in H. pylori-infected compared to uninfected patients. COX-2 inhibition significantly increased expression of Th1 transcription factors along with production of IL-12 and IFN-γ. By contrast, no changes in the expression of STAT6 and production of IL-4 were found. Conclusion: This study provides a mechanism by which H. pylori may actually interfere with normal T-cell activation in human gastric mucosa, possibly enhancing its pathogenicity. The use of COX-2 selective inhibitors as immunomodulators in the course of H. pylori infection deserves investigations. [ABSTRACT FROM AUTHOR]

Much interest has been shown in the relationship between Helicobacter pylori infection and gastric carcinogenesis. It is becoming clearer that H. pylori strains carrying a functional cag pathogenicity island (cagPAI), which encodes the type IV secretion system (TFSS) and its effector CagA, play an important role in the development of gastric carcinoma. Furthermore, genetic polymorphism present in the cagA gene appears to influence the degree of an individual cagPAI-positive H. pylori to elicit gastric mucosal lesions, and this process is significantly affected by host genetic polymorphisms such as proinflammatory cytokine gene polymorphisms. Pathomechanism of gastric carcinogenesis associated with H. pylori includes bacteria-host interaction leading to morphologic alterations such as atrophic gastritis and gastrointestinal metaplasia mediated by COX-2 overexpression, cancer cell invasion, and neo-angiogenesis via TLR2/TLR9 system and transcription factors (e.g., NF-κB) activation. In addition, H. pylori infection triggers adhesion molecule expression and activity and produces an enhancement in oxidative stress interacting with gastric production of appetite hormone ghrelin and nonsteroidal anti-inflammatory drugs. [ABSTRACT FROM AUTHOR]

Helicobacter pyloriextrudes protein- and lipopolysaccharide-enriched outer membrane vesicles from its cell surface which have been postulated to act to deliver virulence factors to the host. Lewis antigen expression by lipopolysaccharide ofH. pyloricells has been implicated in a number of pathogenic roles. The aim of this study was to further characterize the expression of lipopolysaccharide on the surface of these outer membrane vesicles and, in particular, expression of Lewis antigens and their association with antibody production in the host.H. pyloristrains were examined for outer membrane vesicle production using transmission electron microscopy and Lewis antigen expression probed using immunoelectron microscopy. Sera from patients were analyzed for cross-reacting anti-Lewis antibodies and, subsequently, absorbed using outer membrane vesicle preparations to remove the cross-reacting antibodies.The formation of outer membrane vesicles byH. pyloriwas observed in both in vitro and in vivo samples. Furthermore, vesicles were produced following culture in either liquid or solid medium by all strains examined. Moreover, we observed the presence of Lewis epitopes on outer membrane vesicles using immunoelectron microscopy and immunoblotting. Circulating anti-Lewis antibodies were found in the sera of gastric cancer patients but not in the sera ofH. pylori-negative control subjects. Absorption of patient sera with outer membrane vesicles decreased the levels of anti-Lewis autoantibodies.Our results demonstrate the ability ofH. pylorito generate outer membrane vesicles bearing serologically recognizable Lewis antigens on lipopolysaccharide molecules which may contribute to the chronic immune stimulation of the host. The ability of these vesicles to absorb anti-Lewis autoantibodies indicates that they may, in part, play a role in putative autoimmune aspects ofH. pyloripathogenesis. [ABSTRACT FROM AUTHOR]

Cyclooxygenase 2 (COX-2) is induced by the presence ofHelicobacter pylori(H. pylori) on the gastric mucosa as part of the inflammatory response; this results in the synthesis of prostaglandins that amplify the local inflammatory response. The presence ofH. pyloriinhibits the secretion of ascorbate into the gastric lumen. Interestingly, ascorbate inhibits the growth ofH. pyloriand low dietary levels are associated with an increased risk of gastric adenocarcinoma. We therefore investigated the effect of ascorbate onH. pylorimediated COX-2 induction and prostaglandin productionin vitro.H. pyloriwas cocultured with gastric epithelial cells in the presence of ascorbate at physiological concentrations. The expression of COX-2 was assessed by Western blotting and prostaglandin E2 (PGE2) was assessed by ELISA.Ascorbate inhibited gastric cell PGE2 synthesis but not in COX-2 expression in response toH. pylori. In the absence of the organism, ascorbate also reduced PGE2 expression in cells that constitutively express COX-2, again with no reduction of COX-2 protein expression.Physiological concentrations of ascorbate inhibit PGE2 but not COX-2 expression in response toH. pyloriin gastric epithelial cells. [ABSTRACT FROM AUTHOR]

Research in the last year has provided new insights into the function of the the cag-associated type IV secretion system and the vacuolating toxin VacA. A quite new aspect was disclosed by the finding that Helicobacter pylori in Mongolian gerbils colonizes a very distinct topology in the gastric mucous layer, obviously providing optimal conditions for long-term survival. Further research activities focused on H. pylori ammonia and metal metabolism as well as on bacterial stress defence mechanisms. Differential expression of approximately 7% of the bacterial genome was found at low pH suggesting that H. pylori has evolved a multitude of acid-adaptive mechanisms. VacA was shown to interrupt phagosome maturation in macrophage cell lines as well as to modulate and interfere with T lymphocyte immunological functions. Gastric mucosa as well as the H. pylori-infected epithelial cell line AGS strongly express IL-8 receptor A and B, which might contribute to the augmentation of the inflammatory response. Accumulating evidence implicates genetic variation in the inflammatory response to H. pylori in the etiology of the increased risk of gastric cancer after H. pylori infection. The chronic imbalance between apoptosis and cell proliferation is the first step of gastric carcinogenesis. In this regard, it was demonstrated that coexpression of two H. pylori proteins, CagA and HspB, in AGS cells, caused an increase in E2F transcription factor, cyclin D3, and phosphorylated retinoblastoma protein. Taken together, we now have a better understanding of the role of different virulence factors of H. pylori. There is still a lot to be learned, but the promising discoveries summarized here, demonstrate that the investigation of the bacterial survival strategies will give novel insights into pathogenesis and disease development. [ABSTRACT FROM AUTHOR]

Cyclooxygenase 2 (COX-2) is an inducible enzyme that plays a key role in the synthesis of prostaglandins in response to inflammatory stimuli. It is expressed in the gastric mucosa as part of the response to infection with Helicobacter pylori. The specific interaction between H. pylori and the gastric epithelium that results in COX-2 expression has not been identified. In order to investigate the hypothesis that lipopolysaccharide (LPS) from H. pylori plays a role in the induction of cyclooxygenase 2 in the stomach, gastric cell lines MKN-7 and MKN-45 were incubated with LPS from either H. pylori NCTC 11637 or Escherichia coli 055:B5. Incubation of cells with live H. pylori NCTC 11637 was also carried out as a positive control. Cells were then analysed for COX-2 protein and mRNA and prostaglandin E2 synthesis. Cyclooxygenase 2 protein and mRNA expression was induced by E. coli LPS and live H. pylori, but not by H. pylori LPS. Prostaglandin E2 synthesis increased in a dose-dependent manner in both cell lines with E. coli but not H. pylori LPS. H. pylori LPS is of low biological activity when compared with E. coli LPS in its ability to induce the expression of cyclooxygenase 2 and synthesis of prostaglandin E2. This may provide one mechanism by which H. pylori minimizes the inflammatory response in the gastric mucosa, allowing chronic infection. [ABSTRACT FROM AUTHOR]

Recent studies in both humans and animal models strongly suggest the contribution of the host immune response to Helicobacter pylori-related disease. Inducible nitric oxide synthase has been shown to be up-regulated in the gastric epithelium during H. pylori gastritis, suggesting a role in inflammation. C57BL/6 wild-type and inducible nitric oxide synthase gene knockout mice were infected with H. pylori strain SS1. Expression of macrophage inflammatory protein-2 (MIP-2), interleukin-1 beta (IL-1β), Th1 (IL-2 and gamma interferon) and Th2 (IL-4 and IL-10) cytokines, and inducible cyclooxygenase mRNA in mice was determined in mouse gastric tissues and quantified using either competitive reverse transcription–polymerase chain reaction or competitive polymerase chain reaction following reverse transcription. The Th1 cytokine gamma interferon was only detected in wild-type and inducible nitric oxide synthase gene knockout infected mice, while a Th2 (IL-4) response was not detected. H. pylori induced MIP-2 and IL-1β mRNA in mice. Because similar levels of inflammatory mediators were noted in both wild-type and nitric oxide synthase gene knockout infected mice, our data suggest that inducible nitric oxide synthase does not influence expression of these inflammatory mediators in the early stages of H. pylori infection in mice. [ABSTRACT FROM AUTHOR]

ABSTRACT Background. The bacterium Helicobacter pylori is associated with a number of gastrointestinal diseases, such as gastric ulcer, duodenal ulcer and gastric cancer. Several histological changes may be observed during the course of infection; some may influence the progression towards cancer. The aim of this study was to build a statistical model to discover direct interactions between H. pylori and different precancerous changes of the gastric mucosa, and in what order and to what degree those may influence the development of the intestinal type of gastric cancer. Methods. To find direct and indirect interactions between H. pylori and different histological variables, log-linear analyses were used on a case–control study. To generate mathematically and biologically relevant statistical models, a designed algorithm and observed frequency tables were used. Results. The results show that patients with H. pylori infection need to present with proliferation and intestinal metaplasia to develop gastric cancer of the intestinal type. Proliferation and intestinal metaplasia interacted with the variables atrophy and foveolar hyperplasia. Intestinal metaplasia was the only variable with direct interaction with gastric cancer. Gender had no effect on the variables examined. Conclusion. The direct interactions observed in the final statistical model between H. pylori , changes of the mucosa and gastric cancer strengthens and supports previous theories about the progression towards gastric cancer. The results suggest that gastric cancer of the intestinal type may develop from H. pylori infection, proliferation and intestinal metaplasia, while atrophy and foveolar hyperplasia interplay with the other histological variables in the disease process. [ABSTRACT FROM AUTHOR]

ABSTRACT Background. Helicobacter pylori CagA is injected into the host cell and tyrosine-phosphorylated. We examined tyrosine-phosphorylation sites of CagA, as well as the function of CagA proteins in vivo and in vitro. Methods. After proteolytic digestion of CagA with lysyl endopeptidase, CagA tyrosine-phosphorylation sites were determined using quadropolar time-of-flight (Q-TOF) mass spectrometry analysis. Specific anti-pY CagA polyclonal and anti-CagA monoclonal antibodies were used to examine gastric mucosal biopsy specimens from H. pylori infected patients. Results. Mass spectrometry identified five crucial tyrosine-phosphorylation sites of CagA at Tyr893, Tyr912, Tyr965, Tyr999, and Tyr1033 within the five repeated EPIYA sequences of H. pylori (NCTC11637)-infected AGS cells. CagA protein also had an immuno-receptor tyrosine-based activation motif (ITAM)-like amino acid sequences in the 3′ region of the cagA , E PIY ATI x27 EIY ATI , which closely resembled the ITAM. CagA proteins: (i) were localized to the 1% TritonX-100 resistant membrane fraction (lipid rafts); (ii) formed a cluster of phosphorylated CagA protein complexes; (iii) associated with tyrosine-phosphorylated GIT1/Cat1 (G protein-coupled receptor kinase-interactor 1/Cool-associated tyrosine-phosphorylated 1), substrate molecules of receptor type protein-tyrosine phosphatase (RPTPζ/β), which is the receptor of VacA; and (iv) were involved in a delay and negative regulation of VacA-induced signal. Furthermore, immunohistochemical staining of gastric mucosal biopsy specimens provided strong evidence that tyrosine-phosphorylated CagA is found together with CagA at the luminal surface of gastric foveola in vivo. Conclusion. These findings suggest an important role for CagA containing ITAM-like sequences in the pathogenesis of H. pylori- related disease. [ABSTRACT FROM AUTHOR]

Abstract Five years after publication of the complete genome sequence of Helicobacter pylori , research interest is shifting from the descriptive association of virulence factors with clinical outcome in infected patients to the molecular mechanisms of virulence factor action. This is particularly noticeable for VacA and CagA, for both of which detailed understanding of the interaction with host signalling pathways has accumulated over the last year. The role of H. pylori Lewis antigens for clinical outcome was further substantiated. Various strategies of H. pylori to fool or evade the human immune system are described, which all lead to the dysfunction of specific compartments of the host cellular immune system. Finally, a number of animal models indicate that inflammation is a key factor for gastric carcinogenesis, which is finally supported by a large prospective study identifying corpus atrophy and intestinal metaplasia as precancerous conditions. [ABSTRACT FROM AUTHOR]

Abstract Background. Nitric oxide (NO) generated by nitric oxide synthase (NOS) is known to be an important modulator of the mucosal inflammatory response. In this study, we questioned whether Helicobacter pylori infection could up-regulate the epithelial cell inducible NOS (iNOS) gene expression and whether NO production could show polarity that can be regulated by immune mediators. Materials and Methods. Human gastric epithelial cell lines were infected with H. pylori , and the iNOS mRNA expression was assessed by quantitative RT-PCR. NO production was assayed by determining nitrite/nitrate levels in culture supernatants. To determine the polarity of NO secretion by the H. pylori -infected epithelial cells, Caco-2 cells were cultured as polarized monolayers in transwell chambers, and NO production was measured. Results. iNOS mRNA levels were significantly up-regulated in the cells infected with H. pylori , and expression of iNOS protein was confirmed by Western blot analysis. Increased NO production in the gastric epithelial cells was seen as early as 18 hours postinfection, and reached maximal levels by 24 hours postinfection. The specific MAP kinase inhibitors decreased H. pylori -induced iNOS and NO up-regulation. After H. pylori infection of polarized epithelial cells, NO was released predominantly into the apical compartment, and IL-8 was released predominantly into basolateral compartment. The addition of IFN-γ to H. pylori -infected polarized epithelial cells showed a synergistically higher apical and basolateral NO release. Conclusion. These results suggest that apical NO production mediated by MAP kinase in H. pylori -infected gastric epithelial cells may influence the bacteria and basolateral production of NO and IL-8 may play a role in the tissue inflammation. [ABSTRACT FROM AUTHOR]

Background. The infection with cagA-positive Helicobacter pylori strains is reported to be associated with peptic ulcer disease in developed countries, but it is controversial in Asia. To investigate the relationship between the virulence factors of H. pylori and peptic ulcer disease in Japan, we compared these between ulcer and nonulcer patients. Materials and Methods. Seventy-four strains of clinically isolated H. pylori obtained from 22 gastric ulcer (GU), 23 duodenal ulcer (DU), and 29 chronic gastritis (CG) patients were studied. The presence of vacA and cagA gene was examined by polymerase chain reaction method using two different primer sets. We evaluated the proliferation-inhibiting and lethal cytotoxicity of culture supernatants using the alamarBlue assay. Results. The vacA gene was identified in all strains by the original primers. S1 strains were found in 90.9% (20/22) from GU, 95.7% (22/23) from DU, and 96.6% (28/29) from CG patients. The prevalence of cagA gene determined by the first, and second primers was 90.9% (20/22), 90.9% (20/22) in strains from GU, 87.0% (20/23), 91.3% (21/23) from DU, and 86.2% (25/29), 89.7% (26/29) from CG patients, respectively. The supernatant showed cytolethal effect in 95.5% (21/22) of strains from GU, in 100% (23/23) from DU, and in 93.1% (27/29) from CG patients. There was no significant difference in the prevalence of the virulence factors between H. pylori strains isolated from patients with peptic ulcers and those with chronic gastritis. Conclusions. These results indicate that cagA gene status and the proliferation-inhibiting and lethal cytotoxicity of supernatant are not reliable markers of ulcerogenicity of H. pylori in Japanese patients. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori, gastric cancer‐causing bacteria, survive in their gastric environment of more than 50% of the world population. The presence of H. pylori in the gastric vicinity promotes the development of various diseases including peptic ulcer and gastric carcinoma. H. pylori produce and secret Vacuolating cytotoxin A (VacA), a major toxin facilitating the bacteria against the host defense system. The toxin causes multiple effects in epithelial cells and immune cells, especially T cells, B cells, and Macrophages. Methods: This review describes the diverse functionalities of protein toxin VacA. The specific objective of this review is to address the overall structure, mechanism, and functions of VacA in various cell types. The recent advancements are summarized and discussed and thus conclusion is drawn based on the overall reported evidences. Results: The searched articles on H. pylori VacA were evaluated and limited up to 66 articles for this review. The articles were divided into four major categories including articles on vacA gene, VacA toxin, distinct effects of VacA toxin, and their effects on various cells. Based on these studies, the review article was prepared. Conclusions: This review describes an overview of how VacA is secreted by H. pylori and contributes to colonization and virulence in multiple ways by affecting epithelial cells, T cells, Dendritic cells, B cells, and Macrophages. The reported evidence suggests that the comprehensive outlook need to be developed for understanding distinctive functionalities of VacA. [ABSTRACT FROM AUTHOR]