Table of Contents Author Guidelines Submit a Manuscript
Mediators of Inflammation
Volume 2014, Article ID 426309, 9 pages
http://dx.doi.org/10.1155/2014/426309
Review Article

H. pylori Virulence Factors: Influence on Immune System and Pathology

Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany

Received 11 October 2013; Accepted 19 December 2013; Published 21 January 2014

Academic Editor: Alojz Ihan

Copyright © 2014 Behnam Kalali et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Helicobacter pylori is the most widespread chronic bacterial agent in humans and is well recognized for its association with ulcer disease and gastric cancer, with both representing major global health and socioeconomic issues. Given the high level of adaptation and the coevolution of this bacterium with its human host, a thorough and multidirectional view of the specific microbiological characteristics of this infection as well as the host physiology is needed in order to develop novel means of prevention of therapy. This review aims to pinpoint some of these potentially important angles, which have to be considered mutually when studying H. pylori’s pathogenicity. The host’s biological changes due to the virulence factors are a valuable pillar of H. pylori research as are the mechanisms by which bacteria provoke these changes. In this context, necessary adhesion molecules and significant virulence factors of H. pylori are discussed. Moreover, metabolism of the bacteria, one of the most important aspects for a better understanding of bacterial physiology and consequently possible therapeutic and prophylactic strategies, is addressed. On the other hand, we discuss the recent experimental proofs of the “hygiene hypothesis” in correlation with Helicobacter’s infection, which adds another aspect of complexity to this infection.

1. Introduction

Helicobacter pylori (H. pylori) is a helix shaped, microaerophilic, Gram-negative, flagellated bacteria. This bacterium is one of the most important human pathogens, infecting more than 50% of the human population. H. pylori and mankind have had an ancient relationship for at least 50,000 years [1]. Infection with H. pylori is usually acquired in early childhood and persists for life [2]. While over 80% of infected individuals are asymptomatic [3], the infection can lead to peptic ulcer, gastritis, and gastric cancer. Thus, being recognized as the principal agent leading to gastric cancer, WHO has classified H. pylori as a class I carcinogen. H. pylori uniquely colonizes the stomach where it induces inflammation and affects gastric physiology. There are well-characterized mechanisms of adaptation, which ancestral H. pylori have developed over the time. Through selection and coevolution, this bacterium established measures by which it actively and passively avoids the human immune response. Given the widespread prevalence of this infection, its socioeconomic impact, and the rising antibiotic resistance rates worldwide, novel means of treatment and prevention will be required. Therefore, it is essential to understand the unique metabolism capabilities, virulence factors as well as immune evasion mechanism of this bacterium, and its impact on human defense machinery.

The genome of this organism was fully sequenced in 1997 [4, 5], which facilitated and accelerated further studies on the biology, pathology, and immunology of H. pylori infection. Interestingly, its genome has a size of only one-third of E-coli’s genome [6], possibly reflecting the high degree of specialization of this bacterium. Beside H. pylori’s impressive tools which directly affect host cells and its binding molecules that facilitate anchoring of the bacterium to its host, the bacterium possesses metabolic factors which enable it to successfully alter the extreme environmental niche for its own benefit. Furthermore, there are comprehensive but mostly epidemiologic studies, describing a symbiotic relationship between man and Helicobacter. In the present review we will focus on bacterial factors involved in adhesion, pathogenesis, and inflammation as well as some key aspects of H. pylori metabolism, which will provide an insight into the biology of the bacterium and its symbiotic relationship with its human host.

2. H. pylori’s Adhesins

Adhesins are bacterial cell-surface proteins that enable bacterial adherence to cells. The adherence of pathogens to mucosal epithelial cells is the first step required for both colonization and pathogenesis. The adherence of H. pylori to the gastric mucosa is important for protection from mechanisms like acidic pH, mucus, and exfoliation [7]. H. pylori adhesins are considered as bacterial virulence factors and are involved in numerous processes during early and chronic phases of infection. They also contribute to the differential outcome in infected patients by triggering disease development. H. pylori adhesive factors belong to the largest outer membrane protein (OMP) family of the bacterium, namely, the Hop family. The Hop family contains the most well-known adhesins of H. pylori like BabA, SabA, AlpA/B, HopZ, and OipA.

2.1. BabA

The first identified and probably best characterized adhesin of H. pylori is a 78 KDa protein termed BabA (blood group antigen binding adhesion). BabA (HopS or OMP28) can bind to human (α-1, 3/4-difucosylated) and related terminal fucose residues on blood group antigens O (H antigen), A, and B on gastric epithelial cells [8, 9]. These initial studies were further substantiated in larger cohorts, which showed a coevolution and adaptation of this adherence factor with human blood group antigens serving as receptors [1012].

At present babA1 and babA2, which encode BabA, have been cloned [13], of which babA2 is the functionally active gene. It has been shown that the presence of babA gene correlates with the presence of cagA (cytotoxin-associated gene A) and vacA (vacuolating cytotoxin gene A), and the presence of all three genes increases the risk of gastritis, as well as the ulcer disease, gastric cancer, and MALT lymphoma [14]. On the molecular level, the BabA-mediated adherence to gastric epithelial cells is as an important pathogenic mechanism, which can influence the course of disease through aggravation of inflammatory responses in the stomach [12]. BabA/ binding seems also involved in the induction of double-strand breaks of DNA and consequently DNA damage in host cells [15]. The immunological analysis of the inflammatory responses in the stomach revealed that BabA-positive strains colonize more densely and induce stronger IL-8 secretion in the mucosa compared to BabA-deficient strains [16]. Gerbils infected with BabA+  H. pylori strains showed higher levels of mucosal injury compared to BabA low-expressing or none-expressing strains [17]. BabA mediated binding of H. pylori to can trigger cagPAI-dependent host cell signaling and consecutive production of proinflammatory cytokines [18]. Interestingly studies in rhesus monkeys [19] and Mongolian gerbils [17] have shown that BabA expression is lost during longer course of infection, possibly because other adherence mechanisms take over. This could explain that changes in outer membrane protein expression may play a substantial role in H. pylori adaption to host gastric epithelium for promoting optimal adherence during chronic infection.

2.2. SabA

The sialic acid-binding adhesin HopP or OMP17 is a 70 kDa adhesin of H. pylori which binds to sialyl-dimeric-Lewis x () [20]. After initial colonization mediated by BabA, H. pylori infection leads to upregulation of expression, enabling SabA mediated binding. Interestingly, eradication of H. pylori decreases the expression level [21]. Moreover the adherence of H. pylori to extracellular matrix protein laminin is mediated by SabA [22].

The SabA adhesin can further bind the sialylated carbohydrates on granulocytes and induce an oxidative burst in these cells [23]. Moreover SabA binds to the sialylated structures expressed on erythrocytes and leads to hemagglutination [10]. The colonization density of H. pylori in patients lacking was maintained due to the SabA. Thus, in patients with weak or no expression, expression on the gastric epithelium plays a compensatory role in the maintenance of H. pylori colonization. [24].

2.3. AlpA/B

The highly homologous genes alpa and alpb encode the adherence associated lipoproteins AlpA (HopC or OMP20) and AlpB (HopB or OMP21) [4, 25]. The coproduced AlpA and AlpB proteins are involved in adhering to gastric tissue [26, 27]. Both proteins can bind to mouse laminin in vitro [28] and can induce the induction of IL-6 and IL-8 in gastric cell lines [29]. The absence of AlpA or AlpB not only reduced the bacterial load in the stomach in a guinea pig and gerbil model of H. pylori infection [30, 31] but also led to lower bacterial colonization in C57BL/6 mice [29]. At present no host receptor has been detected for either of these adhesins.

2.4. HopZ

Immunofluorescence studies have shown the presence of HopZ (74 kDa) on H. pylori cells. Furthermore, HopZ appears to mediate adherence to gastric epithelial cell lines as bacterial binding is significantly reduced in HopZ knock-out strains [32]. The exact function of HopZ is however still unclear. In a guinea pig model of H. pylori infection, the HopZ mutant strains did not affect the stomach colonization [31]. Conversely, HopZ inactivation reduced the ability of H. pylori to survive in the stomach in a transgenic mouse strain but not in the wild type controls in a model of chronic atrophic gastritis [33]. The host receptor for HopZ is as yet unknown.

2.5. OipA

The outer inflammatory protein A (HopH or OMP13) is a 35 kDa proinflammatory protein. The exact role of OipA is still not clear. While OipA was able to increase IL-8 secretion from gastric epithelial cell lines [34] and its combined function with cag PAI (the cag pathogenicity island) induced inflammation through phosphorylation of different signaling pathways [3538], the mutant OipA strain could not alter in vitro IL-8 secretion from gastric cell lines [39], and inflammation in gerbils infected with OipA mutant strains was not attenuated [40]. The functional OipA expression of H. pylori is associated with duodenal ulcers and gastric cancer [4042]. At present no host receptor for OipA has been identified.

3. H. pylori Virulence Factors Involved in Gastric Inflammation

The chronic inflammation elicited by H. pylori in the gastric mucosa plays a major role in the development of gastric cancer. Several bacterial virulence factors contribute to the inflammatory response towards H. pylori either by altering host-signaling pathways important to maintain tissue homeostasis in epithelial cells or by differentially stimulating innate immune cells. Of those, the cag pathogenicity island (PAI), CagA, and VacA are the best characterized. However, other bacterial determinants as γ-glutamyltranspeptidase (gGT), the duodenal ulcer-promoting gene (dupA), or peptidoglycan have been also shown to be important inducers of gastric inflammation.

3.1. CagPAI

Virulence strains of H. pylori possess the cagPAI. This 40 kb region contains 31 potential coding regions [43], which encode for the different components of a type IV secretion system (T4SS). Some of those components are essential for CagA translocation such as CagT [44] while others additionally play an important role in the host’s inflammatory response. For instance, DNA recombination in CagY was found to alter the function of the T4SS and proposed to modulate the host immune response to promote bacterial persistence [45], while CagL induces inflammation by interacting with host integrins and inducing IL-8 secretion in a CagA translocation and NOD1-independent manner [46].

After assembly of the T4SS and pilus formation, CagA is translocated into host cells where it can undergo phosphorylation at EPIYA sites [47] by two types of kinases: SRC and ABL. SRC kinases mediate the initial phosphorylation of CagA, preferentially at EPIYA-C (and EPIYA-D) motifs, while ABL kinases phosphorylate any EPIYA site later during the course of infection [48]. Phosphorylated and nonphosphorylated CagA can interact with several host proteins and thus alter host cell signaling, playing a crucial role in H. pylori-induced inflammation. Several studies indicate that CagA can directly activate NF-B and induce the release of IL-8 [49, 50]. Moreover, NF-B activation and inflammation was significantly enhanced in the gastric mucosa of Mongolian gerbils infected with H. pylori CagA proficient bacteria. However, other studies suggest that activation of NF-B and IL-8 expression are dependent on the T4SS but CagA independent at early time points [51]. Nevertheless, while direct activation of NF-B and IL-8 upregulation remains controversial, it is clear that the presence of cagPAI drives the proinflammatory response of gastric epithelial cells. CagA is not only injected into gastric epithelial cells, but it can be also injected into B lymphoid cells [52] and murine and human dendritic cells (DCs) [53, 54]. Interestingly, CagA translocation into DCs suppresses host immune response by reducing the secretion of proinflammatory cytokines as IL-12p40 and enhancing the expression of the suppressive cytokine IL-10 [54], indicating a dual pro- and anti-inflammatory role for CagA during H. pylori infection dependent on the cellular context.

In addition to CagA, peptidoglycan can also be delivered into host cells through the T4SS and outer membrane vesicles [55]. Recognition of peptidoglycan by NOD1 induces the production of proinflammatory cytokines MIP-2, β-defensins, and IL-8 through activation of NF-B, p38, and Erk signaling in the host cells [56, 57]. Furthermore, activation of NOD1 by peptidoglycan regulates the production of type I interferon, which can affect Th1 cell differentiation [58]. Modifications in its structure seem to be essential for dampening host immune detection and contribute to bacterial persistence [59, 60]. Moreover, reduced mucosal cytokine response was detected in NOD1 deficient mice infected with cagPAI positive H. pylori strains [56], indicating that peptidoglycan-NOD1 signaling is important in the immune response towards H. pylori.

3.2. VacA

All H. pylori strains carry the vacA gene, which codes for the secreted pore-forming protein VacA. Expression levels, cell type specific toxicity, and disease severity are linked to sequence variation in different domains of VacA [61]. VacA is secreted by the bacterium via a type V autotransport secretion system and enters the host cells by endocytosis. Once internalized, VacA accumulates inside different cellular compartment and induces apoptosis [62]. In addition, VacA disrupts epithelial cell tight connections and is distributed in the lamina propria where it encounters T cells recruited to the sites of infection. As a result T cell proliferation and effector functions are inhibited, allowing persistence of the bacterium [63]. VacA has also been reported to have an indirect effect on T cells; the mechanisms are as yet unknown. VacA can induce DC tolerance and regulatory T cell induction; however this effect has not been yet documented in human cells [64]. Although VacA influences the host inflammatory response mainly by suppressing T cell activation, the toxin also induces a proinflammatory effect on T cells which is mediated by activation of NF-B and leads to upregulation of IL-8 [65]. Additionally, disruption of autophagy elicited by VacA is another mechanism by which it can cause gastric inflammation [66].

3.3. gGT

gGT is constitutively expressed by all H. pylori strains and gGT presence was shown to be essential for the establishment of the infection in mice [67]. It was shown that a H. pylori secreted-low molecular weight protein suppressed T cell proliferation [68]. Later studies identified this inhibitory factor as gGT and showed that disruption of the Ras signaling pathway was the molecular mechanism employed by gGT to induce T cell cycle arrest [69]. More recent data in murine models of infection as well as our own unpublished results in human dendritic cells indicate that gGT contributes to DC tolerization, skewing the T cell response towards a regulatory phenotype [64]. Nevertheless, further investigations are required in order to elucidate how gGT induces DC tolerance. In addition, gGT contributes to gastric inflammation via generation of H2O2, subsequent activation of NF-B, and upregulation of IL-8 in primary gastric epithelial cells [70]. In a more recent report Rimbara et al. propose glutamine deprivation induced by gGT to be responsible for induction of gastric inflammation and to increase the risk of developing gastric cancer [71].

3.4. dupA

dupA is an interesting and as yet not fully characterized H. pylori virulence factor involved in inflammation. An association between dupA and increased expression levels of IL-8 has been observed in the gastric mucosa of H. pylori-infected subjects [7274], but neither dupA1 nor dupA2 were found to induce IL-8 secretion by gastric epithelial cells. dupA1 was found, however, to increase proinflammatory cytokine expression, most markedly IL-12p40, IL-12p70, and IL-23 by CD14+ mononuclear cells, which may explain how dupA1 contributes to gastric inflammation [73].

4. Metabolism of H. pylori

In addition to potential virulence factors and adhesion molecules with a direct effect on host cells, mostly explained above, there are some further metabolic mechanisms that are not per set considered as virulence factors. These must be taken into account as potential therapeutic or prophylactic targets in the context of chronic colonization of human stomach. H. pylori is a microaerophilic organism that requires a small amount of oxygen (3 to 7 percent) for its metabolic activities and cannot be grown at higher oxygen concentrations like fully aerobic microorganisms [75]. Through whole genome sequencing of H. pylori in experimental studies of the bacterial metabolism, it has been inferred that several pathways are missing for the biosynthesis of essential amino acids, lipids, and nucleotides in comparison to other microorganisms like E. coli. Whilst amino acids and lipids can also be potential sources of carbon and energy [76, 77], glucose appears to be the only source of carbohydrate utilized by the bacterium [78]. It has been reported that H. pylori exploits not only oxidative phosphorylation but also fermentation processes [79]. H. pylori, like other living organisms, requires metal ions, specifically cobalt, iron, and nickel, mostly for activity or synthesis of its enzymes [8082]. Furthermore, H. pylori infection may cause metabolic disorders of the host, such as iron deficiency anemia, due to either direct absorption of these trace elements by bacterium or by hampering their uptake or trafficking [8385].

At the time of H. pylori’s discovery by Marshall and Warren, it was reported that this bacterium did not possess the fermentative mechanism and was unable to catalyze carbohydrates [86]. Just a few years later Mendz and Hazell discovered enzymes of the pentose phosphate pathway as well as glucokinase, which were the first suggestions that H. pylori had the ability to utilize glucose [87]. Phosphorylated glucose is processed through the pentose phosphate pathway. Its metabolite ribose 5-phosphate is essential for DNA synthesis and repairs [88]. Alternatively, glucose 6-phosphate enters the Entner-Doudoroff pathway and results in pyruvate production [89]. The fate of pyruvate in H. pylori has been the subject of several studies [79, 90, 91]. It may be metabolized to acetyl coenzyme-A (acetyl-CoA) and enter the krebs’ cycle to produce succinate or fatty acid synthesis, or it may pass the fermentation and lead to the production of acetate, ethanol, fumarate, and lactate [57, 8289, 8994]. While some enzymes involved in these metabolic pathways like fumarate reductase are described as potential targets for vaccine development, some downstream metabolites like acetaldehyde (produced by aldehyde—and alcohol dehydrogenase) are known virulence factors.

Amino acids are considered as the main source of nitrogen and to a lesser extent potential carbon and energy reserves of the bacterium. More simply, when glucose or the metabolic enzymes involved in its pathways are lacking, H. pylori is able to catalyze amino acids such as arginine, aspartate, asparagine glutamine, and serine and use them as basic nutrients [76, 90]. Some surprisingly novel insights regarding enzymes as well as the metabolites involved in amino acid metabolism have been uncovered in subsequent investigations after descriptions of amino acid requirements [76, 95] and their metabolism. Certain unique properties result in some of these, like γ-glutamyltranspeptidase, catalase, high temperature requirement A (HtrA), and fumarate reductase being described as virulence factors and they have been considered as potential candidates for therapeutic as well as prophylactic approaches against H. pylori [67, 94, 9698]. In addition to amino acids, H. pylori is able to utilize other substrates like urea and ammonia as source of nitrogen [4, 76]. Amino nitrogen is essential for the synthesis of other biomolecules, and early studies have demonstrated that urea derived nitrogen is incorporated into amino acids [99, 100]. Out of many extensive investigations regarding urea and urease, it is important to point out that the presence of large amounts of urease in the cytoplasm and also in the extracellular milieu of H. pylori is unique [101]. Urease is constitutively expressed by H. pylori and comprises more than 10% of the whole protein content produced by H. pylori [102]. This highly active enzyme is the main responsible factor for the production of ammonia, which beside involvement in biosynthesis also acts in acid resistance [102]. It has been clearly shown that urease is a critical virulence factor essential for the colonization of stomach. These specific properties have designated an exclusive position for urease in vaccine research [103, 104] and must inform successful diagnostic approaches for H. pylori [105107]. It should be stressed that in this paper only a few metabolic mechanisms connected to the virulence of H. pylori are mentioned. Other reviews provide a comprehensive description of the H. pylori’s metabolism [2, 87, 88].

5. Symbiotic Relation between H. pylori and Human

The prevalence of H. pylori infection is higher in developing countries than that in developed countries. There is evidence that while prevalence of H. pylori infection is decreasing in many countries due to improvements in sanitation and living conditions, the prevalence of allergic diseases like asthma and rhinitis has increased by 32% in Western populations [108, 109]. Such a dramatic increase within a relatively short period of time cannot be attributed to genetic determinants alone. Hence, environmental factors are thought to act as major risk factors for the development of asthma. The inverse relationship between infectious and atopic diseases in Western countries has paralleled decreasing rates of serious infections due to both increased hygiene standards and the expanded availability of antibiotics. This relationship between infection and allergic diseases has led to the formation of the hygiene hypothesis [110]. More recent studies attribute this relationship to a shift of balance between effector T cell subtypes towards Th2-helper cells in the absence of early exposure towards pathogens [111, 112]. Taken together, these observations suggest that the observed increase in the prevalence of asthma may be linked to a decrease in infections, while certain pathogens like respiratory viruses may actually enhance the development of asthma [113, 114]. Although the current data mostly relies on epidemiological associations, a few functional or mechanistic links have been established [111, 115]. In this context, several recent studies have investigated the association of H. pylori infection and allergic disease, and increasing data are indicative of an inverse association of H. pylori with asthma and allergy [116, 117]. The acquisition of H. pylori in childhood seems to be linked to reduced asthma and allergy risk [118]. Recently, a huge cross-sectional analysis, using data from 7412 participants in the National Health and Nutrition Examination Survey (NHANES), revealed that H. pylori seropositivity was inversely associated with onset of asthma before 5 years of age and current asthma in children aged 3–13 years [119]. Despite the strong statistical power of the study, these results are still intensively debated [120, 121]. This is perhaps to be expected given the socioeconomic impact of both diseases. It is important to point out that strategies aiming at broadly eradicating H. pylori in order to prevent gastric cancer might have unexpected consequences on asthma prevalence. Therefore, not only is a multilateral knowledge of H. pylori as a complex pathogen necessary, but also, as Martin Blaser states, “Prospective studies are needed to understand causal relationships and to help ascertain intermediate mechanisms” [122].

6. Conclusion

A better understanding of “multidirectional” aspects and features of H. pylori’s biology is of fundamental interest to develop strategies helping us to cope with this infection. This minireview attempts to emphasize some of these different features. While the importance and impact of H. pylori’s biochemical virulence factors on host physiology are not negligible, adhesion molecules and mechanisms by which the bacterium can anchor and nestle in the human stomach are similarly meaningful. Additionally a comprehensive knowledge of the unique metabolism of the bacterium will help in identifying possible foibles which may be applicable for future therapies. The complex combination of environmental, host, and bacterial factors determines the susceptibility and severity of outcome of H. pylori infection and related pathology in the subset of individuals. Important epidemiological as well as new experimental findings have confirmed the validity of the “Hygiene hypothesis” also in relation with H. pylori. These data and future studies revealing the distinct beneficial mechanism of H. pylori’s contribution to the “Hygiene hypothesis” will guide us in developing new drugs for allergic and immune relevant applications. Additionally, new diagnostic tests suitable for screening of larger populations will facilitate to establish risk adjusted guidelines of H. pylori control.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. J. C. Atherton and M. J. Blaser, “Coadaptation of Helicobacter pylori and humans: ancient history, modern implications,” The Journal of Clinical Investigation, vol. 119, no. 9, pp. 2475–2487, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. J. G. Kusters, A. H. M. van Vliet, and E. J. Kuipers, “Pathogenesis of Helicobacter pylori infection,” Clinical Microbiology Reviews, vol. 19, no. 3, pp. 449–490, 2006. View at Publisher · View at Google Scholar · View at Scopus
  3. M. J. Blaser, “Who are we? Indigenous microbes and the ecology of human diseases,” EMBO Reports, vol. 7, no. 10, pp. 956–960, 2006. View at Publisher · View at Google Scholar · View at Scopus
  4. J. F. Tomb, O. White, A. R. Kerlavage et al., “The complete genome sequence of the gastric pathogen Helicobacter pylori,” Nature, vol. 388, no. 6642, pp. 539–547, 1997. View at Google Scholar
  5. R. A. Alm, L.-S. L. Ling, D. T. Moir et al., “Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori,” Nature, vol. 397, no. 6715, pp. 176–180, 1999. View at Publisher · View at Google Scholar · View at Scopus
  6. F. R. Blattner, G. Plunkett III, C. A. Bloch et al., “The complete genome sequence of Escherichia coli K-12,” Science, vol. 277, no. 5331, pp. 1453–1462, 1997. View at Publisher · View at Google Scholar · View at Scopus
  7. A. J. Smolka and S. Backert, “How Helicobacter pylori infection controls gastric acid secretion,” Journal of Gastroenterology, vol. 47, no. 6, pp. 609–618, 2012. View at Publisher · View at Google Scholar · View at Scopus
  8. M. Aspholm-Hurtig, G. Dailide, M. Lahmann et al., “Functional adaptation of BabA the H. pylori ABO blood group antigen binding adhesin,” Science, vol. 305, no. 5683, pp. 519–522, 2004. View at Publisher · View at Google Scholar · View at Scopus
  9. T. Borén, P. Falk, K. A. Roth, G. Larson, and S. Normark, “Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens,” Science, vol. 262, no. 5141, pp. 1892–1895, 1993. View at Google Scholar · View at Scopus
  10. M. Aspholm, F. O. Olfat, J. Nordén et al., “SabA is the H. pylori hemagglutinin and is polymorphic in binding to sialylated glycans,” PLoS Pathogens, vol. 2, no. 10, article e110, 2006. View at Publisher · View at Google Scholar · View at Scopus
  11. F. O. Olfat, Q. Zheng, M. Oleastro et al., “Correlation of the Helicobacter pylori adherence factor BabA with duodenal ulcer disease in four European countries,” FEMS Immunology and Medical Microbiology, vol. 44, no. 2, pp. 151–156, 2005. View at Publisher · View at Google Scholar · View at Scopus
  12. C. Prinz, M. Schöniger, R. Rad et al., “Key importance of the Helicobacter pylori adherence factor blood group antigen binding adhesin during chronic gastric inflammation,” Cancer Research, vol. 61, no. 5, pp. 1903–1909, 2001. View at Google Scholar · View at Scopus
  13. D. Ilver, A. Arnqvist, J. Ögren et al., “Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging,” Science, vol. 279, no. 5349, pp. 373–377, 1998. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Gerhard, N. Lehn, N. Neumayer et al., “Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 22, pp. 12778–12783, 1999. View at Publisher · View at Google Scholar · View at Scopus
  15. I. M. Toller, K. J. Neelsen, M. Steger et al., “Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 36, pp. 14944–14949, 2011. View at Publisher · View at Google Scholar · View at Scopus
  16. R. Rad, M. Gerhard, R. Lang et al., “The Helicobacter pylori blood group antigen-binding adhesin facilitates bacterial colonization and augments a nonspecific immune response,” Journal of Immunology, vol. 168, no. 6, pp. 3033–3041, 2002. View at Google Scholar · View at Scopus
  17. T. Ohno, A. Vallström, M. Rugge et al., “Effects of blood group antigen-binding adhesin expression during Helicobacter pylori infection of Mongolian gerbils,” Journal of Infectious Diseases, vol. 203, no. 5, pp. 726–735, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. N. Ishijima, M. Suzuki, H. Ashida et al., “BabA-mediated adherence is a potentiator of the helicobacter pylori type IV secretion system activity,” The Journal of Biological Chemistry, vol. 286, no. 28, pp. 25256–25264, 2011. View at Publisher · View at Google Scholar · View at Scopus
  19. J. V. Solnick, L. M. Hansen, N. R. Salama, J. K. Boonjakuakul, and M. Syvanen, “Modification of Helicobacter pylori outer membrane protein expression during experimental infection of rhesus macaques,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 7, pp. 2106–2111, 2004. View at Publisher · View at Google Scholar · View at Scopus
  20. J. Mahdavi, B. Sondén, M. Hurtig et al., “Helicobacter pylori sabA adhesin in persistent infection and chronic inflammation,” Science, vol. 297, no. 5581, pp. 573–578, 2002. View at Publisher · View at Google Scholar · View at Scopus
  21. J. Sakamoto, T. Watanabe, T. Tokumaru, H. Takagi, H. Nakazato, and K. O. Lloyd, “Expression of Lewisa, Lewisb, Lewis(x), Lewis(y), sialyl-Lewisa, and sialyl-Lewis(x) blood group antigens in human gastric carcinoma and in normal gastric tissue,” Cancer Research, vol. 49, no. 3, pp. 745–752, 1989. View at Google Scholar · View at Scopus
  22. A. Walz, S. Odenbreit, J. Mahdavi, T. Borén, and S. Ruhl, “Identification and characterization of binding properties of Helicobacter pylori by glycoconjugate arrays,” Glycobiology, vol. 15, no. 7, pp. 700–708, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. M. Unemo, M. Aspholm-Hurtig, D. Ilver et al., “The sialic acid binding SabA adhesin of Helicobacter pylori is essential for nonopsonic activation of human neutrophils,” The Journal of Biological Chemistry, vol. 280, no. 15, pp. 15390–15397, 2005. View at Publisher · View at Google Scholar · View at Scopus
  24. B.-S. Sheu, S. Odenbreit, K.-H. Hung et al., “Interaction between host gastric sialyl-Lewis x and H. pylori SabA enhances H. pylori density in patients lacking gastric Lewis B antigen,” American Journal of Gastroenterology, vol. 101, no. 1, pp. 36–44, 2006. View at Publisher · View at Google Scholar · View at Scopus
  25. R. A. Alm, J. Bina, B. M. Andrews, P. Doig, R. E. W. Hancock, and T. J. Trust, “Comparative genomics of Helicobacter pylori: analysis of the outer membrane protein families,” Infection and Immunity, vol. 68, no. 7, pp. 4155–4168, 2000. View at Publisher · View at Google Scholar · View at Scopus
  26. S. Odenbreit, M. Till, and R. Haas, “Optimized BlaM-transposon shuttle mutagenesis of Helicobacter pylori allows the identification of novel genetic loci involved in bacterial virulence,” Molecular Microbiology, vol. 20, no. 2, pp. 361–373, 1996. View at Publisher · View at Google Scholar · View at Scopus
  27. S. Odenbreit, M. Till, D. Hofreuter, G. Faller, and R. Haas, “Genetic and functional characterization of the alpAB gene locus essential for the adhesion of Helicobacter pylori to human gastric tissue,” Molecular Microbiology, vol. 31, no. 5, pp. 1537–1548, 1999. View at Publisher · View at Google Scholar · View at Scopus
  28. O. A. Senkovich, J. Yin, V. Ekshyyan et al., “Helicobacter pylori AlpA and AlpB Bind host laminin and influence gastric inflammation in gerbils,” Infection and Immunity, vol. 79, no. 8, pp. 3106–3116, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Lu, Y. W. Jeng, E. J. Beswick et al., “Functional and intracellular signaling differences associated with the Helicobacter pylori AlpAB adhesin from Western and East Asian strains,” The Journal of Biological Chemistry, vol. 282, no. 9, pp. 6242–6254, 2007. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Sugimoto, T. Ohno, D. Y. Graham, and Y. Yamaoka, “Helicobacter pylori outer membrane proteins on gastric mucosal interleukin 6 and 11 expression in Mongolian gerbils,” Journal of Gastroenterology and Hepatology, vol. 26, no. 11, pp. 1677–1684, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. R. de Jonge, Z. Durrani, S. G. Rijpkema, E. J. Kuipers, A. H. M. Van Vliet, and J. G. Kusters, “Role of the Helicobacter pylori outer-membrane proteins AlpA and AlpB in colonization of the guinea pig stomach,” Journal of Medical Microbiology, vol. 53, no. 5, pp. 375–379, 2004. View at Publisher · View at Google Scholar · View at Scopus
  32. B. Peck, M. Ortkamp, K. D. Diehl, E. Hundt, and B. Knapp, “Conservation, localization and expression of HopZ, a protein involved in adhesion of Helicobacter pylori,” Nucleic Acids Research, vol. 27, no. 16, pp. 3325–3333, 1999. View at Publisher · View at Google Scholar · View at Scopus
  33. M. Giannakis, H. Bäckhed, S. L. Chen et al., “Response of gastric epithelial progenitors to Helicobacter pylori isolates obtained from Swedish patients with chronic atrophic gastritis,” The Journal of Biological Chemistry, vol. 284, no. 44, pp. 30383–30394, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. Y. Yamaoka, D. H. Kwon, and D. Y. Graham, “A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 13, pp. 7533–7538, 2000. View at Publisher · View at Google Scholar · View at Scopus
  35. Y. Yamaoka, T. Kudo, H. Lu, A. Casola, A. R. Brasier, and D. Y. Graham, “Role of interferon-stimulated responsive element-like element in interleukin-8 promoter in Helicobacter pylori infection,” Gastroenterology, vol. 126, no. 4, pp. 1030–1043, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. H. Lu, J. Y. Wu, T. Kudo, T. Ohno, D. Y. Graham, and Y. Yamaoka, “Regulation of interleukin-6 promoter activation in gastric epithelial cells infected with Helicobacter pylori,” Molecular Biology of the Cell, vol. 16, no. 10, pp. 4954–4966, 2005. View at Publisher · View at Google Scholar · View at Scopus
  37. F. H. Tabassam, D. Y. Graham, and Y. Yamaoka, “OipA plays a role in Helicobacter pylori-induced focal adhesion kinase activation and cytoskeletal re-organization,” Cellular Microbiology, vol. 10, no. 4, pp. 1008–1020, 2008. View at Publisher · View at Google Scholar · View at Scopus
  38. F. H. Tabassam, D. Y. Graham, and Y. Yamaoka, “Helicobacter pylori activate epidermal growth factor receptor- and phosphatidylinositol 3-OH kinase-dependent Akt and glycogen synthase kinase 3β phosphorylation,” Cellular Microbiology, vol. 11, no. 1, pp. 70–82, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. A. Dossumbekova, C. Prinz, J. Mages et al., “Helicobacter pylori HopH (OipA) and bacterial pathogenicity: genetic and functional genomic analysis of hopH gene polymorphisms,” Journal of Infectious Diseases, vol. 194, no. 10, pp. 1346–1355, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. A. T. Franco, E. Johnston, U. Krishna et al., “Regulation of gastric carcinogenesis by Helicobacter pylori virulence factors,” Cancer Research, vol. 68, no. 2, pp. 379–387, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. R. Markovska, L. Boyanova, D. Yordanov, G. Gergova, and I. Mitov, “Helicobacter pylori oipA genetic diversity and its associations with both disease and cagA, vacA s, m, and i alleles among Bulgarian patients,” Diagnostic Microbiology and Infectious Disease, vol. 71, no. 4, pp. 335–340, 2011. View at Publisher · View at Google Scholar · View at Scopus
  42. Y. Yamaoka, S. Kikuchi, H. M. T. ElZimaity, O. Gutierrez, M. S. Osato, and D. Y. Graham, “Importance of Helicobacter pylori oipA in clinical presentation, gastric inflammation, and mucosal interleukin 8 production,” Gastroenterology, vol. 123, no. 2, pp. 414–424, 2002. View at Publisher · View at Google Scholar · View at Scopus
  43. S. Censini, C. Lange, Z. Xiang et al., “Cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 25, pp. 14648–14653, 1996. View at Google Scholar · View at Scopus
  44. H. Ding, H. Zeng, L. Huang et al., “Helicobacter pylori chaperone-like protein CagT plays an essential role in the translocation of CagA into host cells,” Journal of Microbiology and Biotechnology, vol. 22, no. 10, pp. 1343–1349, 2012. View at Google Scholar
  45. R. M. Barrozo, C. L. Cooke, L. M. Hansen et al., “Functional plasticity in the type IVsecretion system of Helicobacter pylori,” PLoS Pathogens, vol. 9, no. 2, Article ID e1003189, 2013. View at Google Scholar
  46. R. J. Gorrell, J. Guan, Y. Xin et al., “A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by the Helicobacter pylori type IV secretion system,” Cellular Microbiology, 2012. View at Publisher · View at Google Scholar
  47. T. Hayashi, H. Morohashi, and M. Hatakeyama, “Bacterial EPIYA effectors-where do they come from? What are they? Where are they going?” Cellular Microbiology, vol. 15, no. 3, pp. 377–385, 2013. View at Google Scholar
  48. D. Mueller, N. Tegtmeyer, S. Brandt et al., “c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains,” The Journal of Clinical Investigation, vol. 122, no. 4, pp. 1553–1566, 2012. View at Publisher · View at Google Scholar · View at Scopus
  49. D. W. Kang, W. C. Hwang, M. H. Park et al., “Rebamipide abolishes Helicobacter pylori CagA-induced phospholipase D1 expression via inhibition ofNFkappaB and suppresses invasion of gastric cancer cells,” Oncogene, vol. 32, no. 30, pp. 3531–3542, 2013. View at Google Scholar
  50. K. S. Papadakos, I. S. Sougleri, A. F. Mentis, E. Hatziloukas, and D. N. Sgouras, “Presence of terminal EPIYA phosphorylation motifs in Helicobacter pylori CagA contributes to IL-8 secretion, irrespective of the number of repeats,” PLoS One, vol. 8, no. 2, Article ID e56291, 2013. View at Google Scholar
  51. O. Sokolova, M. Borgmann, C. Rieke, K. Schweitzer, H.-J. Rothkötter, and M. Naumann, “Helicobacter pylori induces type 4 secretion system-dependent, but CagA-independent activation oflkappaBs and NF-kappaB/RelA at early time points,” International Journal of Medical Microbiology, vol. 303, no. 8, pp. 548–552, 2013. View at Google Scholar
  52. W.-C. Lin, H.-F. Tsai, S.-H. Kuo et al., “Translocation of Helicobacter pylori CagA into human B lymphocytes, the origin of mucosa-associated lymphoid tissue lymphoma,” Cancer Research, vol. 70, no. 14, pp. 5740–5748, 2010. View at Publisher · View at Google Scholar · View at Scopus
  53. R. Kaebisch, R. Mejías-Luque, C. Prinz, and M. Gerhard, “Helicobacter pylori cytotoxin-associated gene A impairs human dendritic cell maturation and function through IL-10–mediated activation of STAT3,” Journal of Immunology, vol. 192, no. 1, pp. 316–323, 2014. View at Google Scholar
  54. H. Tanaka, M. Yoshida, S. Nishiumi et al., “The CagA protein of Helicobacter pylori suppresses the functions of dendritic cell in mice,” Archives of Biochemistry and Biophysics, vol. 498, no. 1, pp. 35–42, 2010. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Kaparakis, L. Turnbull, L. Carneiro et al., “Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells,” Cellular Microbiology, vol. 12, no. 3, pp. 372–385, 2010. View at Publisher · View at Google Scholar · View at Scopus
  56. E. Vial and J. Pouysségur, “Regulation of tumor cell motility by ERK mitogen-activated protein kinases,” Annals of the New York Academy of Sciences, vol. 1030, pp. 208–218, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. C. C. Allison, T. A. Kufer, E. Kremmer, M. Kaparakis, and R. L. Ferrero, “Helicobacter pylori induces MAPK phosphorylation and AP-1 activation via a NOD1-dependent mechanism,” Journal of Immunology, vol. 183, no. 12, pp. 8099–8109, 2009. View at Publisher · View at Google Scholar · View at Scopus
  58. T. Watanabe, N. Asano, S. Fichtner-Feigl et al., “NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway,” The Journal of Clinical Investigation, vol. 120, no. 5, pp. 1645–1662, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. G. Wang, L. F. Lo, L. S. Forsberg, and R. J. Maier, “Helicobacter pylori peptidoglycan modifications confer lysozyme resistance and contribute to survival in the host,” MBio, vol. 3, no. 6, pp. 00409–00412, 2012. View at Google Scholar
  60. G. Wang, S. E. Maier, L. F. Lo, G. Maier, S. Dosi, and R. J. Maier, “Peptidoglycan deacetylation in Helicobacter pylori contributes to bacterial survival by mitigating host immune responses,” Infection and Immunity, vol. 78, no. 11, pp. 4660–4666, 2010. View at Google Scholar
  61. S. L. Palframan, T. Kwok, and K. Gabriel, “Vacuolating cytotoxin A (VacA), a key toxin for Helicobacter pylori pathogenesis,” Frontiers in Cellular and Infection Microbiology, vol. 2, article 92, 2012. View at Google Scholar
  62. J. Rassow and M. Meinecke, “Helicobacter pylori VacA: a new perspective on an invasive chloride channel,” Microbes and Infection, vol. 14, no. 12, pp. 1026–1033, 2012. View at Google Scholar
  63. A. Muller, M. Oertli, and I. C. Arnold, “H. pylori exploits and manipulates innate and adaptive immune cell signaling pathways to establish persistent infection,” Cell Communication and Signaling, vol. 9, article 25, 2011. View at Google Scholar
  64. M. Oertli, M. Noben, D. B. Engler et al., “Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 8, pp. 3047–3052, 2013. View at Google Scholar
  65. E. Takeshima, K. Tomimori, R. Takamatsu et al., “Helicobacter pylori VacA activates NF-κB in T cells via the classical but not alternative pathway,” Helicobacter, vol. 14, no. 4, pp. 271–279, 2009. View at Publisher · View at Google Scholar · View at Scopus
  66. D. Raju, S. Hussey, M. Ang et al., “Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote helicobacter pylori infection in humans,” Gastroenterology, vol. 142, no. 5, pp. 1160–1171, 2012. View at Publisher · View at Google Scholar · View at Scopus
  67. C. Chevalier, J.-M. Thiberge, R. L. Ferrero, and A. Labigne, “Essential role of Helicobacter pylori γ-glutamyltranspeptidase for the colonization of the gastric mucosa of mice,” Molecular Microbiology, vol. 31, no. 5, pp. 1359–1372, 1999. View at Google Scholar · View at Scopus
  68. M. Gerhard, C. Schmees, P. Voland et al., “A secreted low-molecular-weight protein from Helicobacter pylori induces cell-cycle arrest of T cells,” Gastroenterology, vol. 128, no. 5, pp. 1327–1339, 2005. View at Publisher · View at Google Scholar · View at Scopus
  69. C. Schmees, C. Prinz, T. Treptau et al., “Inhibition of T-cell proliferation by Helicobacter pylori gamma-glutamyl transpeptidase,” Gastroenterology, vol. 132, no. 5, pp. 1820–1833, 2007. View at Publisher · View at Google Scholar · View at Scopus
  70. M. Gong, S. S. M. Ling, S. Y. Lui, K. G. Yeoh, and B. Ho, “Helicobacter pylori γ-glutamyl transpeptidase is a pathogenic factor in the development of peptic ulcer disease,” Gastroenterology, vol. 139, no. 2, pp. 564–573, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. E. Rimbara, S. Mori, H. Kim, and K. Shibayama, “Role of gamma-glutamyl transpeptidase in the pathogenesis of Helicobacter pylori infection,” Microbiology and Immunology, vol. 57, no. 10, pp. 665–673, 2013. View at Publisher · View at Google Scholar
  72. S. W. Jung, M. Sugimoto, S. Shiota, D. Y. Graham, and Y. Yamaoka, “The intact dupA cluster is a more reliable Helicobacter pylori virulence marker than dupA alone,” Infection and Immunity, vol. 80, no. 1, pp. 381–387, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. N. R. Hussein, R. H. Argent, C. K. Marx, S. R. Patel, K. Robinson, and J. C. Atherton, “Helicobacter pylori dupA is polymorphic, and its active form induces proinflammatory cytokine secretion by mononuclear cells,” Journal of Infectious Diseases, vol. 202, no. 2, pp. 261–269, 2010. View at Publisher · View at Google Scholar · View at Scopus
  74. D. M. M. Queiroz, G. A. Rocha, A. M. C. Rocha et al., “DupA polymorphisms and risk of Helicobacter pylori-associated diseases,” International Journal of Medical Microbiology, vol. 301, no. 3, pp. 225–228, 2011. View at Publisher · View at Google Scholar · View at Scopus
  75. N. Kangatharalingam and P. S. Amy, “Helicobacter pylori comb.nov. exhibits facultative acidophilism and obligate microaerophilism,” Applied and Environmental Microbiology, vol. 60, no. 6, pp. 2176–2179, 1994. View at Google Scholar · View at Scopus
  76. G. L. Mendz and S. L. Hazell, “Aminoacid utilization by Helicobacter pylori,” International Journal of Biochemistry and Cell Biology, vol. 27, no. 10, pp. 1085–1093, 1995. View at Publisher · View at Google Scholar · View at Scopus
  77. A. Marais, L. Monteiro, and F. Megraud, “Microbiology of Helicobacter pylori,” Current Topics in Microbiology and Immunology, vol. 241, pp. 103–122, 1999. View at Google Scholar
  78. G. L. Mendz and S. L. Hazell, “Glucose phosphorylation in Helicobacter pylori,” Archives of Biochemistry and Biophysics, vol. 300, no. 1, pp. 522–525, 1993. View at Publisher · View at Google Scholar · View at Scopus
  79. G. L. Mendz, S. L. Hazell, and L. van Gorkom, “Pyruvate metabolism in Helicobacter pylori,” Archives of Microbiology, vol. 162, no. 3, pp. 187–192, 1994. View at Publisher · View at Google Scholar · View at Scopus
  80. S. Benoit and R. J. Maier, “Dependence of Helicobacter pylori urease activity on the nickel-sequestering ability of the UreE accessory protein,” Journal of Bacteriology, vol. 185, no. 16, pp. 4787–4795, 2003. View at Publisher · View at Google Scholar · View at Scopus
  81. D. J. McGee, J. Zabaleta, R. J. Viator, T. L. Testerman, A. C. Ochoa, and G. L. Mendz, “Purification and characterization of Helicobacter pylori arginase, RocF: unique features among the arginase superfamily,” European Journal of Biochemistry, vol. 271, no. 10, pp. 1952–1962, 2004. View at Publisher · View at Google Scholar · View at Scopus
  82. A. Danielli and V. Scarlato, “Regulatory circuits in Helicobacter pylori: network motifs and regulators involved in metal-dependent responses,” FEMS Microbiology Reviews, vol. 34, no. 5, pp. 738–752, 2010. View at Publisher · View at Google Scholar · View at Scopus
  83. J. Dovhanj, K. Kljaic, M. Smolic, and D. Svagelj, “NADPH and Iron may have an important role in attenuated mucosal defense in Helicobacter pylori infection?” Mini-Reviews in Medicinal Chemistry, vol. 10, no. 14, pp. 1309–1315, 2010. View at Publisher · View at Google Scholar · View at Scopus
  84. H. Monzon, M. Forné, M. Esteve, M. Rosinach, and C. Loras, “Helicobacter pylori infection as a cause of iron deficiency anaemia of unknown origin,” World Journal of Gastroenterology, vol. 19, no. 26, pp. 4166–4171, 2013. View at Google Scholar
  85. K. Muhsen and D. Cohen, “Helicobacter pylori infection and iron stores: a systematic review and meta-analysis,” Helicobacter, vol. 13, no. 5, pp. 323–340, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. B. J. Marshall and J. R. Warren, “Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration,” The Lancet, vol. 1, no. 8390, pp. 1311–1315, 1984. View at Google Scholar · View at Scopus
  87. S. L. Hazell and G. L. Mendz, “How Helicobacter pylori works: an overview of the metabolism of Helicobacter pylori,” Helicobacter, vol. 2, no. 1, pp. 1–12, 1997. View at Google Scholar · View at Scopus
  88. A. Marais, G. L. Mendz, S. L. Hazell, and F. Mégraud, “Metabolism and genetics of Helicobacter pylori: the genome era,” Microbiology and Molecular Biology Reviews, vol. 63, no. 3, pp. 642–674, 1999. View at Google Scholar · View at Scopus
  89. P. A. Chalk, A. D. Roberts, and W. M. Blows, “Metabolism of pyruvate and glucose by intact cells of Helicobacter pylori studied by13C NMR spectroscopy,” Microbiology, vol. 140, no. 8, pp. 2085–2092, 1994. View at Google Scholar · View at Scopus
  90. N. J. Hughes, P. A. Chalk, C. L. Clayton, and D. J. Kelly, “Identification of carboxylation enzymes and characterization of a novel four-subunit pyruvate:flavodoxin oxidoreductase from Helicobacter pylori,” Journal of Bacteriology, vol. 177, no. 14, pp. 3953–3959, 1995. View at Google Scholar · View at Scopus
  91. M. St. Maurice, N. Cremades, M. A. Croxen, G. Sisson, J. Sancho, and P. S. Hoffman, “Flavodoxin:quinone reductase (FqrB): a redox partner of pyruvate:ferredoxin oxidoreductase that reversibly couples pyruvate oxidation to NADPH production in Helicobacter pylori and Campylobacter jejuni,” Journal of Bacteriology, vol. 189, no. 13, pp. 4764–4773, 2007. View at Publisher · View at Google Scholar · View at Scopus
  92. G. L. Mendz, S. L. Hazell, and B. P. Burns, “Glucose utilization and lactate production by Helicobacter pylori,” Journal of General Microbiology, vol. 139, no. 12, pp. 3023–3028, 1993. View at Google Scholar · View at Scopus
  93. G. L. Mendz, S. L. Hazell, and B. P. Burns, “The Entner-Doudoroff pathway in Helicobacter pylori,” Archives of Biochemistry and Biophysics, vol. 312, no. 2, pp. 349–356, 1994. View at Publisher · View at Google Scholar · View at Scopus
  94. Z. Ge, Y. Feng, C. A. Dangler, S. Xu, N. S. Taylor, and J. G. Fox, “Fumarate reductase is essential for Helicobacter pylori colonization of the mouse stomach,” Microbial Pathogenesis, vol. 29, no. 5, pp. 279–287, 2000. View at Publisher · View at Google Scholar · View at Scopus
  95. D. J. Reynolds and C. W. Penn, “Characteristics of Helicobacter pylori growth in a defined medium and determination of its amino acid requirements,” Microbiology, vol. 140, no. 10, pp. 2649–2656, 1994. View at Google Scholar · View at Scopus
  96. M. Löwer, C. Weydig, D. Metzler et al., “Prediction of extracellular proteases of the human pathogen Helicobacter pylori reveals proteolytic activity of the Hp1018/19 protein HtrA,” PLoS ONE, vol. 3, no. 10, Article ID e3510, 2008. View at Publisher · View at Google Scholar · View at Scopus
  97. T. U. Westblom, S. Phadnis, W. Langenberg, K. Yoneda, E. Madan, and B. R. Midkiff, “Catalase negative mutants of Helicobacter pylori,” European Journal of Clinical Microbiology and Infectious Diseases, vol. 11, no. 6, pp. 522–526, 1992. View at Google Scholar · View at Scopus
  98. K. J. McGovern, T. G. Blanchard, J. A. Gutierrez, S. J. Czinn, S. Krakowka, and P. Youngman, “γ-glutamyltransferase is a Helicobacter pylori virulence factor but is not essential for colonization,” Infection and Immunity, vol. 69, no. 6, pp. 4168–4173, 2001. View at Publisher · View at Google Scholar · View at Scopus
  99. R. L. Ferrero, S. L. Hazell, and A. Lee, “The urease enzymes of Campylobacter pylori and a related bacterium,” Journal of Medical Microbiology, vol. 27, no. 1, pp. 33–40, 1988. View at Google Scholar · View at Scopus
  100. C. L. Williams, T. Preston, M. Hossack, C. Slater, and K. E. L. McColl, “Helicobacter pylori utilises urea for amino acid synthesis,” FEMS Immunology and Medical Microbiology, vol. 13, no. 1, pp. 87–94, 1996. View at Publisher · View at Google Scholar · View at Scopus
  101. W. Hong, K. Sano, S. Morimatsu et al., “Medium pH-dependent redistribution of the urease of Helicobacter pylori,” Journal of Medical Microbiology, vol. 52, no. 3, pp. 211–216, 2003. View at Google Scholar
  102. P. Bauerfeind, R. Garner, B. E. Dunn, and H. L. T. Mobley, “Synthesis and activity of Helicobacter pylori urease and catalase at low pH,” Gut, vol. 40, no. 1, pp. 25–30, 1997. View at Google Scholar · View at Scopus
  103. M. D. Dipetrillo, T. Tibbetts, H. Kleanthous, K. P. Killeen, and E. L. Hohmann, “Safety and immunogenicity of phoP/phoQ-deleted Salmonella typhi expressing Helicobacter pylori urease in adult volunteers,” Vaccine, vol. 18, no. 5-6, pp. 449–459, 1999. View at Publisher · View at Google Scholar · View at Scopus
  104. K. Hirota, K. Nagata, Y. Norose et al., “Identification of an antigenic epitope in Helicobacter pylori urease that induces neutralizing antibody production,” Infection and Immunity, vol. 69, no. 11, pp. 6597–6603, 2001. View at Publisher · View at Google Scholar · View at Scopus
  105. D. Y. Graham, P. D. Klein, and D. J. Evans Jr., “Campylobacter pylori detected noninvasively by the 13C-urea breath test,” The Lancet, vol. 1, no. 8543, pp. 1174–1177, 1987. View at Google Scholar · View at Scopus
  106. S. W. Moon, T. H. Kim, H. S. Kim et al., “United rapid urease test is superior than separate test in detecting Helicobacter pylori at the gastric antrum and body specimens,” Clinical Endoscopy, vol. 45, no. 4, pp. 392–396, 2012. View at Google Scholar
  107. L. C. Fry, “Comparison of l3C- urea blood test to 13C-breath test and rapid urease test for the diagnosis of Helicobacter pylori infection,” Acta Gastroenterol Latinoam, vol. 35, no. 4, pp. 225–229, 2005. View at Google Scholar
  108. R. Beasley, J. Crane, C. K. W. Lai, and N. Pearce, “Prevalence and etiology of asthma,” Journal of Allergy and Clinical Immunology, vol. 105, no. 2, part 2, pp. S466–S472, 2000. View at Google Scholar · View at Scopus
  109. W. Eder, M. J. Ege, and E. von Mutius, “The asthma epidemic,” The New England Journal of Medicine, vol. 355, no. 21, pp. 2226–2235, 2006. View at Publisher · View at Google Scholar · View at Scopus
  110. D. P. Strachan and C. H. Sanders, “Damp housing and childhood asthma; respiratory effects of indoor air temperature and relative humidity,” Journal of Epidemiology and Community Health, vol. 43, no. 1, pp. 7–14, 1989. View at Google Scholar · View at Scopus
  111. I. C. Arnold, N. Dehzad, S. Reuter et al., “Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells,” The Journal of Clinical Investigation, vol. 121, no. 8, pp. 3088–3093, 2011. View at Publisher · View at Google Scholar · View at Scopus
  112. L. E. Layland, K. Straubinger, M. Ritter et al., “Schistosoma mansoni-mediated suppression of allergic airway inflammation requires patency and Foxp3+ Treg cells,” PLoS Neglected Tropical Diseases, vol. 7, no. 8, article e2379, 2013. View at Google Scholar
  113. N. W. J. Schröder and M. Arditi, “The role of innate immunity in the pathogenesis of asthma: evidence for the involvement of Toll-like receptor signaling,” Journal of Endotoxin Research, vol. 13, no. 5, pp. 305–312, 2007. View at Publisher · View at Google Scholar · View at Scopus
  114. L. S. van Rijt, C. H. Geurts Van Kessel, I. Boogaard, and B. N. Lambrecht, “Respiratory viral infections and asthma pathogenesis: a critical role for dendritic cells?” Journal of Clinical Virology, vol. 34, no. 3, pp. 161–169, 2005. View at Publisher · View at Google Scholar · View at Scopus
  115. C. Taube and A. Muller, “The role of Helicobacter pylori infection in the development of allergic asthma,” Expert Review of Respiratory Medicine, vol. 6, no. 4, pp. 441–449, 2012. View at Google Scholar
  116. Y. Chen and M. J. Blaser, “Inverse associations of Helicobacter pylori with asthma and allergy,” Archives of Internal Medicine, vol. 167, no. 8, pp. 821–827, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. J. Reibman, M. Marmor, J. Filner et al., “Asthma is inversely associated with Helicobacter pylori status in an urban population,” PLoS ONE, vol. 3, no. 12, Article ID e4060, 2008. View at Publisher · View at Google Scholar · View at Scopus
  118. L. Lang, “Childhood acquisition of Helicobacter pylori linked to reduced asthma and allergy risk,” Gastroenterology, vol. 133, no. 1, p. 6, 2007. View at Publisher · View at Google Scholar · View at Scopus
  119. Y. Chen and M. J. Blaser, “Helicobacter pylori colonization is inversely associated with childhood asthma,” Journal of Infectious Diseases, vol. 198, no. 4, pp. 553–560, 2008. View at Publisher · View at Google Scholar · View at Scopus
  120. S. M. Raj, K. E. Choo, A. M. Noorizan, Y. Y. Lee, and D. Y. Graham, “Evidence against Helicobacter pylori being related to childhood asthma,” The Journal of Infectious Diseases, vol. 199, no. 6, pp. 914–915, 2009. View at Publisher · View at Google Scholar · View at Scopus
  121. M. Wjst, “Does Helicobacter pylori protect against asthma and allergy?” Gut, vol. 57, no. 8, pp. 1178–1179, 2008. View at Google Scholar · View at Scopus
  122. M. J. Blaser, Y. Chen, and J. Reibman, “Does Helicobacter pylori protect against asthma and allergy?” Gut, vol. 57, no. 5, pp. 561–567, 2008. View at Publisher · View at Google Scholar · View at Scopus