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Gut Microbes. 2010 Mar-Apr; 1(2): 119–127.
Published online 2010 April 8. doi:  10.4161/gmic.1.2.11991
PMCID: PMC2958064

Surreptitious manipulation of the human host by Helicobacter pylori


Microbial pathogens contribute to the development of more than 1 million cases of cancer per year. Gastric adenocarcinoma is the second leading cause of cancer-related death in the world, and gastritis induced by Helicobacter pylori is the strongest known risk factor for this malignancy. H. pylori colonizes the stomach for years, not days or weeks, as is usually the case for bacterial pathogens, and it always induces inflammation; however, only a fraction of colonized individuals ever develop disease. Identification of mechanisms through which H. pylori co-opts host defenses to facilitate its own persistence will not only improve diagnostic and therapeutic modalities, but may also provide insights into other diseases that arise within the context of long-term pathogen-initiated inflammatory states, such as chronic viral hepatitis and hepatocellular carcinoma.

Key words: gastric cancer, bacterial pathogenesis, immune evasion, inflammation, virulence factors


A strong link has been established between chronic H. pylori colonization and a diverse spectrum of diseases, including gastric and duodenal ulceration, gastric adenocarcinoma, mucosa-associated lymphoid tumor (MALToma), and non-Hodgkin's lymphoma of the stomach. However, the cognate niche inhabited by H. pylori, the human stomach, poses numerous barriers that normally prevent sustained microbial colonization including gastric peristalsis, an acidic pH, and inflammation-generated oxidative stress. Further, H. pylori must nimbly escape elimination by the host immune response to effectively persist within the stomach. In addition to constituents required for colonization (Table 1), H. pylori harbors several virulence factors that can influence disease, but pathologic outcomes ultimately depend on a dynamic interplay between bacteria and host over prolonged periods of coexistence.

Table 1
Bacterial factors required for gastric colonization

Overcoming Host Barriers

Acid resistance.

One of the initial obstacles encountered by H. pylori is the harsh, acidic environment of the stomach, which is frequently at or below pH 2. To circumvent this deterrent, H. pylori produces copious amounts of urease, which catalyzes the hydrolysis of urea into ammonia and carbonic acid. Studies in C57BL/6 and nude mice have demonstrated that urease activity is unequivocally required for successful colonization.13 In macaques, infection with H. pylori strains producing low levels of urease activity leads to an expansion of bacterial subpopulations in which urease production is enriched, further emphasizing the importance of urease activity for successful colonization.3

H. pylori can also manipulate the intragastric pH by stimulating the production of IL-1β, a pro-inflammatory cytokine with potent acid-suppressive properties. In H. pylori-infected Mongolian gerbils, gastric mucosal IL-1β levels increase 6–12 weeks post-challenge, which is accompanied by a reciprocal decrease in gastric acid output.4 Administration of recombinant IL-1 receptor antagonist normalizes acid outputs, implicating IL-1β as a pivotal modulator of acid secretion within inflamed gastric mucosa.4 Informative polymorphisms within genes regulating IL-1β production in humans have allowed case-control studies to be performed that relate genotypes to H. pylori-associated diseases. El-Omar et al. were the first to demonstrate that IL-1β polymorphisms associated with increased expression of IL-1β heighten the risk for atrophic gastritis and gastric adenocarcinoma.59 In addition to IL-1β, high-expression alleles of TNFα, another pro-inflammatory cytokine with acid-suppressive properties, also increase the risk for gastric cancer.6,8 Importantly, these relationships are only present among H. pylori-colonized persons and not uninfected individuals, emphasizing the significance of host-environment interactions and inflammation in the progression to gastric cancer.

Motility and chemotaxis.

Another obstacle that must be confronted within the gastric niche is peristalsis. H. pylori invokes several mechanisms to overcome this impediment, including efficient motility, chemotaxis, and the ability to specifically adhere to gastric epithelium. H. pylori possesses between 3–5 polar flagella, which are comprised primarily of FlaA and FlaB subunits. Deletion of flaA results in flagellar truncation and decreased motility in vitro, while in vivo, FlaA as well as other proteins necessary for flagellar assembly are essential for colonization of rodent and piglet models of infection.1012 Unlike FlaA of Salmonella or other Gram-negative pathogens that colonize mucosal surfaces, H. pylori FlaA is a non-inflammatory molecule, which may contribute to long-term persistence.13,14 In contrast to flaA deficient strains, H. pylori mutants lacking expression of the flagellar motor protein MotB, which is also required for motility, are capable of acutely colonizing mice; however, the 50% infectious dose (ID50) is >4 log-fold higher than that observed for wild-type H. pylori and mutants are unable to be recovered >48 hours after co-challenge with wild-type strains.15,16

In addition to flagella-mediated motility, chemotaxis plays a role in the ability of H. pylori to establish residence in the stomach. To sense external stimuli, H. pylori expresses at least four chemotaxis receptor proteins: TlpA, TlpB, TlpC and TlpD. TlpA is a receptor for arginine and sodium bicarbonate while TlpB is required for pH taxis, but the specific activators for TlpC and TlpD are unknown.17,18 In contrast to FlaA or FlaB, loss of Tlp proteins does not alter levels of colonization in wild-type infected animals; however, mutations in tlpB significantly reduce levels of inflammation in infected C57BL/6 mice or gerbils.19,20

H. pylori response regulators are also important in chemotaxis. Mutants defective in the receptor-kinase adaptor CheW, the histidine kinase CheA, or the response regulator CheY are non-chemotactic, but are able to infect mice at low levels.21 CheW appears to be important for initial steps in colonization, as the ID50 is 1–2 log-fold higher than that observed for wild-type strains, although at 6 months post-challenge, colonization levels are similar between mutant and wild-type isolates.21 Further, cheY and cheA mutants induce lower levels of inflammation in mice and, similar to tlpA and tlpB mutants, are not found closely associated with gastric epithelial cells as frequently in vivo when compared to the topography of wild-type H. pylori.20 Collectively, these data suggest a critical role for motility and chemotaxis for initial as well as long-term colonization of the stomach.

Adherence to gastric epithelium.

Though most H. pylori are free-living within the semipermeable mucous gel layer, approximately 20% of the bacterial population binds to gastric epithelial cells which is thought to be important for colonization. Further, the bacteria that bind epithelial cells are found in close apposition to epithelial tight junctions.22,23 Tight junctions are dynamic structures located at the most apical region of cell-cell contact points and play critical roles in maintenance of barrier function, cell polarity, and intercellular adhesion. H. pylori not only adhere to epithelial cells in close proximity to tight junctions22,23 but also alter the localization patterns of component proteins that form junctional complexes, such as occludin, claudins, junctional adhesion molecules (JAMs), and zonula occludens-1 (ZO-1).2330 Occludin has been implicated in the regulation of barrier function and is directly linked to the actin cytoskeleton via its C-terminus and indirectly through its interactions with ZO-1.26,3135 Expression of occludin at the level of the tight junction is disrupted by H. pylori in cultured canine duodenal epithelial cell monolayers, and our laboratory has recently shown that H. pylori induces barrier dysfunction in gastric epithelial cells via urease-mediated dysregulation of occludin.25,26

H. pylori expresses numerous proteins that function as epithelial cell adhesins. One of the most well-studied is the outer membrane protein (OMP) BabA, which is encoded by babA2 and binds Lewisb (Leb) blood-group antigens expressed on gastric epithelial cells (Fig. 1). Though not all H. pylori express BabA, BabA+ strains are associated with an increased risk for gastric cancer.36 Expression of BabA is regulated by slipped strand mispairing during replication as well as intragenomic recombination, which can result in aberrant localization of babA2 into the locus occupied by the closely related gene babB.37,38 Evidence of altered regulation of babA expression in vivo has been demonstrated through H. pylori infection of macaques, which revealed that babA2 could be replaced by babB, leading to an inability of recovered isolates to bind Leb in vitro.37

Figure 1
H. pylori adhesins and host receptors. H. pylori adheres to host gastric epithelial cells via the interaction of bacterial adhesins including BabA and SabA with the host receptors Leb and sialyl-Lex, respectively. The host receptor for OipA has not yet ...

OipA is another H. pylori adhesin that can be regulated by slipped-strand mispairing in a manner similar to BabA.39 Expression of OipA in cell co-culture systems leads to higher levels of production of the pro-inflammatory cytokine IL-8 by infected gastric epithelial cells, while in vivo, OipA expression is associated with more severe inflammation in mice as well as cancer in Mongolian gerbils.39,40 SabA is an H. pylori OMP that binds the sialylated glycan Lex (Fig. 1). In situ studies using tissue from Rhesus monkeys demonstrated that an H. pylori mutant lacking BabA bound gastric epithelium in a pattern that mirrored host sialyl-Lex expression. Further, BabA deficient H. pylori pretreated with sialyl-Lex could bind tissue from Leb-, sialyl-Lex expressing mice but with less than 10% efficiency compared with untreated bacteria.41 Thus, H. pylori OMPs that function as adhesins also appear to be critical regulators of efficient colonization of the host.

Oxidative and nitrosative stress.

Reactive oxygen species such as superoxide and reactive nitrogen intermediates exert damaging effects on proteins, membranes, and DNA, which can have dire consequences for colonizing microbes.42 During the course of colonization, H. pylori induces a robust inflammatory response that leads to production of molecules that can potentially induce oxidative and nitrosative damage. However, H. pylori has developed strategies to overcome these obstacles, including expression of a superoxide dismutase (SodB). SodB catalyzes the conversion of superoxide to H2O2, a substrate that can rapidly be inactivated by peroxide or catalase, and SodB-deficient H. pylori colonize mice at a rate of only 4% compare to colonization rates seen in wild-type strains.43

In addition to SodB, H. pylori expresses three peroxiredoxins: alkyl hydroperoxide reductase (AhpC), thiolperoxidase (Tpx), and bacterioferritin comigratory protein (BCP). Disruption of genes encoding any of these proteins results in a dramatic decrease in the ability to colonize mice.4446 H. pylori also expresses catalase (KatA) which facilitates the conversion of H2O2 into oxygen and water. Mutants lacking this enzyme, or the catalase-associated protein KapA, exhibit an increased sensitivity to H2O2.47 Although the short-term colonization efficiency of catalase mutants is essentially the same as wild-type strains, persistent colonization is only 20–50% of wild-type when assessed 24 weeks post-challenge, suggesting a role for these elements in facilitating chronic colonization within an inflammatory milieu.47,48 Another H. pylori gene, mdaB, encodes a NADPH quinone reductase that also has a role in resisting H2O2-mediated damage and MdaB-deficient H. pylori colonize mice at significantly lower frequency and density when compared to wild-type strains.49

H. pylori NapA was originally reported to function in neutrophil recruitment; however, NapA mutants have also been shown to exhibit decreased resistance to oxidative stress and colonize mice with lower efficiency when compared to wild-type strains.50,51 Additionally, H. pylori mutants deficient in SodB, AhpC or KatA express increased levels of NapA, suggesting that NapA may play a compensatory role in oxidative stress resistance under these conditions.46,52 Finally, H. pylori RocF, which converts arginine to urea and ornithine, has also been shown to be important for evading clearance mechanisms that utilize nitric oxide as well as providing shelter from acid-mediated damage. RocF mutants are 1,000 times more sensitive to acid than wild-type H. pylori, which may be due to conversion of arginine-generated urea to ammonia by urease.53,54 RocF can also compete with macrophages for the iNOS substrate arginine, resulting in decreased host iNOS production thereby permitting clearance by nitric oxide defense mechanisms.55,56

Immune evasion.

The most well-studied defense mechanism mounted by human hosts against microbial infection is the immune response, but as might be predicted for a chronic pathogen, H. pylori possesses numerous mechanisms to overcome this obstacle and establish chronic colonization. Gram-negative bacteria such as H. pylori possess lipopolysaccharide (LPS) as a component of the bacterial cell wall, which typically elicits a robust inflammatory response. However, the LPS of H. pylori is relatively anergic, exhibiting >3 log-fold less endotoxin activity when compared with LPS from other Gram-negative bacteria.5759 In vivo studies indicate that H. pylori LPS may also have a role in modulating the immune response as mice immunized with bacterial sonicate containing LPS elicited a strong Th1 immune response while LPS-depleted sonicates induced a Th2 response.58,60

Another host constituent activated by H. pylori that may dampen the immune response is protease-activated receptor (PAR)-1, a G-protein coupled receptor expressed on many cell types including gastric epithelial cells. A recent study indicates that PAR-1 is protective against H. pylori induced inflammation and that it acts to suppress proinflammatory cytokines including MIP-2 in mice.61

The O-antigen of H. pylori LPS contains various human Lewis antigens including Lex, Ley, Lea and Leb, and inactivation of Lex and Ley-encoding genes prevents H. pylori from colonizing mice.6265 Approximately 85% of H. pylori clinical isolates express Lex and Ley and although both Lex and Ley can be detected on individual strains, one antigen usually predominates.6668 Several studies have demonstrated that H. pylori Lewis antigens can undergo phase variation in vitro6871 and in vivo studies using Rhesus monkeys (which like humans, express Lex and Ley on gastric epithelial cells), demonstrated that the Lewis expression pattern of colonizing bacteria varies in response to the expression pattern of their cognate hosts.72,73 A recent study using transgenic mice expressing Leb also demonstrated that H. pylori recovered from these animals, but not wild type mice, expressed Leb.74 This suggests that Lewis antigens facilitate molecular mimicry of the host and allow H. pylori to escape host immune defenses by preventing the formation of antibodies against shared bacterial and host epitopes.

H. pylori has recently been shown to decrease production of specific heat shock proteins (HSPs) in vitro and within colonized gastric mucosa.75 Since HSPs can modulate both innate and adaptive immune responses, inhibition of HSP production may represent an additional mechanism of immune evasion that promotes long-term colonization. Finally, a subpopulation of H. pylori has been shown to maintain residence within gastric epithelial cells as well as within the lamina propria of gastric mucosa, which may represent sanctuary sites that protect against immune clearance.7678

Strain-Specific Factors Linked with Virulence

Although most persons colonized with H. pylori never develop clinically apparent disease, colonization can lead to the development of peptic ulcer disease and gastric cancer. Numerous studies have revealed that there is substantial genetic variability between H. pylori isolates, and indeed, isolates harvested from a single person are genetically unique.7981 Despite this tremendous degree of diversity, several factors associated with disease have been identified.

The cag pathogenicity island and CagA.

CagA is an immunodominant protein encoded by cagA, the terminal gene within the cag pathogenicity island (PAI), and is one of the most intensely studied virulence factors expressed by H. pylori. The presence of the cag PAI varies among H. pylori populations and is found in approximately 60–70% of strains in the United States.8284 H. pylori cag PAI+ strains are associated with an increased risk for atrophic gastritis, peptic ulcer disease, and distal gastric cancer compared to strains that lack this genetic locus.8592

The cag PAI encodes a type IV secretion system which functions to translocate bacterial components such as cagA into host epithelial cells. CagL is expressed, located at the tip of the pilus, and binds α5β1-integrins on target cells in an RGD dependent manner. This interaction activates FAK (focal adhesion kinase) and Src and has a role in H. pylori-induced IL-8 secretion by host cells.93 Recently, CagA, CagI and CagY have also been demonstrated to bind β1-integrin inducing conformational changes permitting CagA translocation.94 Intracellular CagA can be sequentially phosphorylated by Src and Abl kinases, and phosphorylated CagA activates the eukaryotic phosphatase SHP-2 leading to dephosphorylation of host cell proteins and morphological changes including cellular elongation and cell spreading (Fig. 2).9598 Phosphorylation sites have been identified as EPIYA motifs which are located at the carboxy-terminus of CagA and up to 5 motif copies may be present within a single CagA protein. Four variants of the EPIYA motif have been described: EPIYA-A, -B, -C and -D.96,99,100 EPIYA-A and -B motifs are found in strains throughout the world; in contrast, EPIYA-C motifs segregate with CagA proteins expressed by western strains while EPIYA-D motifs predominate in CagA proteins from strains of East Asian origin. In vitro studies have indicated that the number of C-type phosphorylation motifs is associated with the intensity of CagA phosphorylation, cellular morphological changes, and induction of proinflammatory cytokines.101103 Further, in some studies, a greater number of EPIYA sites is linked to gastric atrophy, intestinal metaplasia and gastric cancer, indicating a role for these sites in pathogenesis.99,102,104,105 The sequence surrounding EPIYA-D motifs matches the consensus sequence for SHP-2 binding perfectly and as a result, strains expressing an East Asian CagA exhibit greater SHP-2 binding leading to increased morphological changes compared with western strains.106 However, unphosphorylated CagA moieties also play important roles in pathogenesis by altering cell signaling, including inducing aberrant activation of β-catenin, disrupting apical-junctional complexes, activating STAT3, and inducing a loss of cell polarity (Fig. 2).9598,107,108

Figure 2
H. pylori CagA and peptidoglycan alter numerous cellular processes. CagA is translocated through the T4SS and binds the tight junction proteins ZO-1 and JAM as well as E-cadherin at adherens junctions leading to loss of cell polarity. CagA can be phosphorylated ...

As previously described, H. pylori is frequently found in close association with epithelial cell tight junctions. At junctional complexes, translocated CagA associates with the tight-junction proteins ZO-1 and junctional adhesion molecule (JAM), leading to disruption of tight junctions and alterations of cell polarity.23,108111 Intracellular CagA also binds to E-cadherin at adherens junctions.110 Disruption of cellular organization has now been shown to be due to aberrant inactivation of the kinase Par1, a regulator of cell polarity.108,111,112 Binding of Par1 by CagA also results in perturbation of microtubule formation and myosin II activation.112

Another bacterial molecule that is translocated by the cag T4SS into host epithelial cells is peptidoglycan, which interacts with the host pattern recognition molecule NOD1. NOD1 functions as an intracellular sensor for peptidoglycan components that originate from Gram-negative bacteria. The interaction of H. pylori peptidoglycan with NOD1 leads to increased NFκB activation, resulting in increased production of inflammatory molecules such as IL-8.113 Translocated peptidoglycan also leads to enhanced PI3K-AKT signaling, which decreases H. pylori-induced apoptosis and increases cell migration, phenotypes that may set the stage for carcinogenesis.114 A recent study has now indicated that H. pylori peptidoglycan can also be delivered intracellularly via bacterial outer membrane vesicles.115

In addition to effects induced by translocated CagA and peptidoglycan, the cag PAI-encoded T4SS per se can also exert effects on host cells. The cag PAI protein CagL interacts directly with host cell integrins, resulting in local membrane ruffling and clustering of integrins into focal adhesion complexes.93 These events lead to FAK and Src kinase activation and CagA phosphorylation, resulting in morphological and cell signaling alterations that are similar to growth factor stimulation (Fig. 2).93

The vacuolating cytotoxin.

Another bacterial factor that is clearly associated with H. pylori-induced disease is the vacuolating cytotoxin VacA. VacA was first identified to harbor toxigenic properties by the demonstration that H. pylori VacA-containing culture supernatants produced vacuolation in eukaryotic cells in vitro.116 VacA is an approximately 140 kDa protein which undergoes proteolytic cleavage to yield an 88 kDa product that can be further cleaved to 33 kDa and 55 kDa fragments that can ultimately assemble into large oligomeric complexes.117121 Unlike cagA, the gene encoding VacA (vacA) is found in all H. pylori strains, but exists as allelic variants that exert differences in epithelial cell responses. Polymorphic sites exist within the signal (s) region, the mid (m) region and the more recently identified intermediate (i) region122124 and vacA s1/m1/i1 variants are more strongly associated with gastric adenocarcinoma.122

Oligomeric VacA complexes can insert into cellular lipid bilayers, forming anion-selective membrane channels.125128 The vacuolating activity of VacA is dependent on formation of these channels in conjunction with weak bases such as ammonium chloride.129131 After membrane insertion, VacA is internalized by a pinocytic-like process, leading to the formation of anion-selective channels in endosomal membranes.124,126,132 Vacuolation relies on numerous host factors previously implicated in endosome formation such as V-ATPase, Rab7, Rac1, dynamin and PIKfyve.133135 VacA also induces alterations in late endocytic compartments which leads to inhibition of EGF degradation, clustering of endocytic compartments, and inhibition of antigen presentation.131,136,137

In addition to inserting into plasma and endocytic membranes, VacA also interacts with mitochondrial membranes leading to a decrease in mitochondral transmembrane potential and release of cytochrome c.138140 One study has indicated that VacA-induced cytochrome c release may be indirect and mediated instead by Bax and Bak activation.141 Transient expression of VacA in HeLa cells results in cleavage of poly-ADP-ribose polymerase (PARP), an indicator of caspase-3 activation.138 Both cytochrome c release and caspase-3 activation are pro-apoptotic events, and this mirrors the apoptotic response observed following incubation of VacA with AGS cells.142,143 Although VacA s1m1 variants induce high levels of apoptosis, VacA s2m1 forms do not, suggesting a role for strain variation in differences in gastric epithelial apoptosis that have been observed among H. pylori-infected persons.142,143

Recent studies have also suggested a role for CagA in modulating the apoptosis-inducing function of VacA.144,145 In Mongolian gerbils, CagA activates the cell survival pathway mediated by the MAPK ERK and induces expression of the anti-apoptoptic protein MCL1 in gastric pit cells.145 Further, unphosphorylated CagA antagonizes VacA-induced apoptosis at the mitochondrial membrane while phosphorylated CagA hinders VacA from reaching targeted intracellular compartments.144 Together, these data suggest a possible model in which VacA has a role in colonization of the gastric niche, but after colonization is established, its activity is modulated by translocated CagA, favoring bacterial persistence and protection against cellular apoptosis.

In addition to influencing cell turnover, VacA plays an important role in suppressing the host immune response to H. pylori. Two studies have demonstrated that VacA interrupts phagosome maturation by recruiting tryptophan-aspartate-containing coat protein (TACO or coronin 1), suggesting that VacA may have a role in protecting H. pylori from phagocytic killing.146,147 However, another study using freshly isolated human monocytes demonstrated no effect of VacA on phagosome fusion or intracellular survival.148 This discrepancy may be due to differences in cell lineages or bacterial strains that were used and additional work is needed to reconcile the results from these studies. Additionally, VacA has been shown to interfere with antigen proteolytic processing in T cells and inhibit antigen presentation through the invariant chain dependent pathway thereby interfering with adaptive immunity.136

VacA also inhibits proliferation of Jurkat T cells by interfering with IL-2 signaling, which is due to inhibition of nuclear factor of activated T-cell (NFAT) activation.149151 Evidence suggests that VacA blocks calcium influx resulting in downregulation of the Ca+-calmodulin-dependent phosphatase calcineurin, which in turn inhibits NFAT transcription activation.149,150 VacA can also inhibit proliferation of primary human CD4+ T cells, independently of NFAT.151 In total, the anti-proliferative effects of VacA may be a mechanism by which T cells activated by H. pylori antigens can be inhibited, allowing H. pylori to escape the adaptive immune response and establish chronic infection.


Gastric adenocarcinoma is strongly associated with the presence of H. pylori, and both microbial and host factors influence the risk for carcinogenesis. Interactions between H. pylori constituents and host epithelial and immune cells play an important role in the development of gastric injury. H. pylori has evolved an array of diverse constituents to subvert obstacles presented by the gastric niche which may consequently induce host responses related to carcinogenesis within the context of long-term microbial colonization. Molecular delineation of pathways activated by such host-microbial interactions will not only improve our understanding of H. pylori-induced carcinogenesis, but may also provide mechanistic insights into other malignancies that arise within the context of inflammatory states (e.g., ulcerative colitis and colon cancer).


1. Tsuda M, Karita M, Morshed MG, Okita K, Nakazawa T. A urease-negative mutant of Helicobacter pylori constructed by allelic exchange mutagenesis lacks the ability to colonize the nude mouse stomach. Infect Immun. 1994;62:3586–3589. [PMC free article] [PubMed]
2. Eaton KA, Gilbert JV, Joyce EA, Wanken AE, Thevenot T, Baker P, et al. In vivo complementation of ureB restores the ability of Helicobacter pylori to colonize. Infect Immun. 2002;70:771–778. [PMC free article] [PubMed]
3. Hansen LM, Solnick JV. Selection for urease activity during Helicobacter pylori infection of rhesus macaques (Macaca mulatta) Infect Immun. 2001;69:3519–3522. [PMC free article] [PubMed]
4. Takashima M, Furuta T, Hanai H, Sugimura H, Kaneko E. Effects of Helicobacter pylori infection on gastric acid secretion and serum gastrin levels in Mongolian gerbils. Gut. 2001;48:765–773. [PMC free article] [PubMed]
5. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398–402. [PubMed]
6. El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB, et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology. 2003;124:1193–1201. [PubMed]
7. Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst. 2002;94:1680–1687. [PubMed]
8. Ando T, El-Omar EM, Goto Y, Nobata K, Watanabe O, Maeda O, et al. Interleukin 1B proinflammatory genotypes protect against gastro-oesophageal reflux disease through induction of corpus atrophy. Gut. 2006;55:158–164. [PMC free article] [PubMed]
9. Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S, et al. A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology. 2003;125:364–371. [PubMed]
10. Josenhans C, Labigne A, Suerbaum S. Comparative ultrastructural and functional studies of Helicobacter pylori and Helicobacter mustelae flagellin mutants: both flagellin subunits, FlaA and FlaB, are necessary for full motility in Helicobacter species. J Bacteriol. 1995;177:3010–3020. [PMC free article] [PubMed]
11. Eaton KA, Suerbaum S, Josenhans C, Krakowka S. Colonization of gnotobiotic piglets by Helicobacter pylori deficient in two flagellin genes. Infect Immun. 1996;64:2445–2448. [PMC free article] [PubMed]
12. Kavermann H, Burns BP, Angermuller K, Odenbreit S, Fischer W, Melchers K, et al. Identification and characterization of Helicobacter pylori genes essential for gastric colonization. J Exp Med. 2003;197:813–822. [PMC free article] [PubMed]
13. Andersen-Nissen E, Smith KD, Strobe KL, Barrett SL, Cookson BT, Logan SM, et al. Evasion of Toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci USA. 2005;102:9247–9252. [PubMed]
14. Gewirtz AT, Yu Y, Krishna US, Israel DA, Lyons SL, Peek RM., Je Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J Infect Dis. 2004;189:1914–1920. [PubMed]
15. Guo BP, Mekalanos JJ. Rapid genetic analysis of Helicobacter pylori gastric mucosal colonization in suckling mice. Proc Natl Acad Sci USA. 2002;99:8354–8359. [PubMed]
16. Ottemann KM, Lowenthal AC. Helicobacter pylori uses motility for initial colonization and to attain robust infection. Infect Immun. 2002;70:1984–1990. [PMC free article] [PubMed]
17. Cerda O, Rivas A, Toledo H. Helicobacter pylori strain ATCC700392 encodes a methyl-accepting chemotaxis receptor protein (MCP) for arginine and sodium bicarbonate. FEMS Microbiol Lett. 2003;224:175–181. [PubMed]
18. Croxen MA, Sisson G, Melano R, Hoffman PS. The Helicobacter pylori chemotaxis receptor TlpB (HP0103) is required for pH taxis and for colonization of the gastric mucosa. J Bacteriol. 2006;188:2656–2665. [PMC free article] [PubMed]
19. McGee DJ, Langford ML, Watson EL, Carter JE, Chen YT, Ottemann KM. Colonization and inflammation deficiencies in Mongolian gerbils infected by Helicobacter pylori chemotaxis mutants. Infect Immun. 2005;73:1820–1827. [PMC free article] [PubMed]
20. Williams SM, Chen YT, Andermann TM, Carter JE, McGee DJ, Ottemann KM. Helicobacter pylori chemotaxis modulates inflammation and bacterium-gastric epithelium interactions in infected mice. Infect Immun. 2007;75:3747–3757. [PMC free article] [PubMed]
21. Terry K, Williams SM, Connolly L, Ottemann KM. Chemotaxis plays multiple roles during Helicobacter pylori animal infection. Infect Immun. 2005;73:803–811. [PMC free article] [PubMed]
22. Hazell SL, Lee A, Brady L, Hennessy W. Campylobacter pyloridis and gastritis: association with intercellular spaces and adaptation to an environment of mucus as important factors in colonization of the gastric epithelium. J Infect Dis. 1986;153:658–663. [PubMed]
23. Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 2003;300:1430–1434. [PMC free article] [PubMed]
24. Krueger S, Hundertmark T, Kuester D, Kalinski T, Peitz U, Roessner A. Helicobacter pylori alters the distribution of ZO-1 and p120ctn in primary human gastric epithelial cells. Pathol Res Pract. 2007;203:433–444. [PubMed]
25. Wroblewski LE, Shen L, Ogden S, Romero-Gallo J, Lapierre LA, Israel DA, et al. Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation. Gastroenterology. 2009;136:236–246. [PMC free article] [PubMed]
26. Fedwick JP, Lapointe TK, Meddings JB, Sherman PM, Buret AG. Helicobacter pylori activates myosin light-chain kinase to disrupt claudin-4 and claudin-5 and increase epithelial permeability. Infect Immun. 2005;73:7844–7852. [PMC free article] [PubMed]
27. Liu Y, Nusrat A, Schnell FJ, Reaves TA, Walsh S, Pochet M, et al. Human junction adhesion molecule regulates tight junction resealing in epithelia. J Cell Sci. 2000;113:2363–2374. [PubMed]
28. Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. 1998;141:1539–1550. [PMC free article] [PubMed]
29. Suzuki K, Kokai Y, Sawada N, Takakuwa R, Kuwahara K, Isogai E, et al. SS1 Helicobacter pylori disrupts the paracellular barrier of the gastric mucosa and leads to neutrophilic gastritis in mice. Virchows Arch. 2002;440:318–324. [PubMed]
30. Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123:1777–1788. [PMC free article] [PubMed]
31. Chen G, Sordillo EM, Ramey WG, Reidy J, Holt PR, Krajewski S, et al. Apoptosis in gastric epithelial cells is induced by Helicobacter pylori and accompanied by increased expression of BAK. Biochem Biophys Res Commun. 1997;239:626–632. [PubMed]
32. Balda MS, Whitney JA, Flores C, Gonzalez S, Cereijido M, Matter K. Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein. J Cell Biol. 1996;134:1031–1049. [PMC free article] [PubMed]
33. McCarthy KM, Skare IB, Stankewich MC, Furuse M, Tsukita S, Rogers RA, et al. Occludin is a functional component of the tight junction. J Cell Sci. 1996;109:2287–2298. [PubMed]
34. Wittchen ES, Haskins J, Stevenson BR. Protein interactions at the tight junction. Actin has multiple binding partners, and ZO-1 forms independent complexes with ZO-2 and ZO-3. J Biol Chem. 1999;274:35179–35185. [PubMed]
35. Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM. The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem. 1998;273:29745–29753. [PubMed]
36. Gerhard M, Lehn N, Neumayer N, Boren T, Rad R, Schepp W, et al. Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc Natl Acad Sci USA. 1999;96:12778–12783. [PubMed]
37. Solnick JV, Hansen LM, Salama NR, Boonjakuakul JK, Syvanen M. Modification of Helicobacter pylori outer membrane protein expression during experimental infection of rhesus macaques. Proc Natl Acad Sci USA. 2004;101:2106–2111. [PubMed]
38. Ilver D, Arnqvist A, Ogren J, Frick IM, Kersulyte D, Incecik ET, et al. Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging. Science. 1998;279:373–377. [PubMed]
39. Yamaoka Y, Kwon DH, Graham DY. A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori. Proc Natl Acad Sci USA. 2000;97:7533–7538. [PubMed]
40. Franco AT, Johnston E, Krishna U, Yamaoka Y, Israel DA, Nagy TA, et al. Regulation of gastric carcinogenesis by Helicobacter pylori virulence factors. Cancer Res. 2008;68:379–387. [PMC free article] [PubMed]
41. Mahdavi J, Sonden B, Hurtig M, Olfat FO, Forsberg L, Roche N, et al. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science. 2002;297:573–578. [PMC free article] [PubMed]
42. Imlay JA. Pathways of oxidative damage. Annu Rev Microbiol. 2003;57:395–418. [PubMed]
43. Seyler RW, Jr, Olson JW, Maier RJ. Superoxide dismutase-deficient mutants of Helicobacter pylori are hypersensitive to oxidative stress and defective in host colonization. Infect Immun. 2001;69:4034–4040. [PMC free article] [PubMed]
44. Wang G, Olczak AA, Walton JP, Maier RJ. Contribution of the Helicobacter pylori thiol peroxidase bacterioferritin comigratory protein to oxidative stress resistance and host colonization. Infect Immun. 2005;73:378–384. [PMC free article] [PubMed]
45. Olczak AA, Olson JW, Maier RJ. Oxidative-stress resistance mutants of Helicobacter pylori. J Bacteriol. 2002;184:3186–3193. [PMC free article] [PubMed]
46. Olczak AA, Seyler RW, Jr, Olson JW, Maier RJ. Association of Helicobacter pylori antioxidant activities with host colonization proficiency. Infect Immun. 2003;71:580–583. [PMC free article] [PubMed]
47. Harris AG, Hinds FE, Beckhouse AG, Kolesnikow T, Hazell SL. Resistance to hydrogen peroxide in Helicobacter pylori: role of catalase (KatA) and Fur, and functional analysis of a novel gene product designated ‘KatA-associated protein', KapA (HP0874) Microbiology. 2002;148:3813–3825. [PubMed]
48. Harris AG, Wilson JE, Danon SJ, Dixon MF, Donegan K, Hazell SL. Catalase (KatA) and KatA-associated protein (KapA) are essential to persistent colonization in the Helicobacter pylori SS1 mouse model. Microbiology. 2003;149:665–672. [PubMed]
49. Wang G, Maier RJ. An NADPH quinone reductase of Helicobacter pylori plays an important role in oxidative stress resistance and host colonization. Infect Immun. 2004;72:1391–1396. [PMC free article] [PubMed]
50. Cooksley C, Jenks PJ, Green A, Cockayne A, Logan RP, Hardie KR. NapA protects Helicobacter pylori from oxidative stress damage, and its production is influenced by the ferric uptake regulator. J Med Microbiol. 2003;52:461–469. [PubMed]
51. Wang G, Hong Y, Olczak A, Maier SE, Maier RJ. Dual Roles of Helicobacter pylori NapA in inducing and combating oxidative stress. Infect Immun. 2006;74:6839–6846. [PMC free article] [PubMed]
52. Olczak AA, Wang G, Maier RJ. Up-expression of NapA and other oxidative stress proteins is a compensatory response to loss of major Helicobacter pylori stress resistance factors. Free Radic Res. 2005;39:1173–1182. [PubMed]
53. Mendz GL, Hazell SL. The urea cycle of Helicobacter pylori. Microbiology. 1996;142:2959–2967. [PubMed]
54. McGee DJ, Radcliff FJ, Mendz GL, Ferrero RL, Mobley HL. Helicobacter pylori rocF is required for arginase activity and acid protection in vitro but is not essential for colonization of mice or for urease activity. J Bacteriol. 1999;181:7314–7322. [PMC free article] [PubMed]
55. Gobert AP, McGee DJ, Akhtar M, Mendz GL, Newton JC, Cheng Y, et al. Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival. Proc Natl Acad Sci USA. 2001;98:13844–13849. [PubMed]
56. Chaturvedi R, Asim M, Lewis ND, Algood HM, Cover TL, Kim PY, et al. L-arginine availability regulates inducible nitric oxide synthase-dependent host defense against Helicobacter pylori. Infect Immun. 2007;75:4305–4315. [PMC free article] [PubMed]
57. Perez-Perez GI, Shepherd VL, Morrow JD, Blaser MJ. Activation of human THP-1 cells and rat bone marrow-derived macrophages by Helicobacter pylori lipopolysaccharide. Infect Immun. 1995;63:1183–1187. [PMC free article] [PubMed]
58. Nielsen H, Birkholz S, Andersen LP, Moran AP. Neutrophil activation by Helicobacter pylori lipopolysaccharides. J Infect Dis. 1994;170:135–139. [PubMed]
59. Birkholz S, Knipp U, Opferkuch W. Stimulatory effects of Helicobacter pylori on human peripheral blood mononuclear cells of H. pylori infected patients and healthy blood donors. Int J Med Microbiol Virol Parasitol Infect Dis. 1993;280:166–176. [PubMed]
60. Taylor JM, Ziman ME, Fong J, Solnick JV, Vajdy M. Possible correlates of long-term protection against Helicobacter pylori following systemic or combinations of mucosal and systemic immunizations. Infect Immun. 2007;75:3462–3469. [PMC free article] [PubMed]
61. Wee JL, Chionh YT, Ng GZ, Harbour SN, Allison C, Pagel CN, et al. Protease-activated receptor-1 downregulates the murine inflammatory and humoral response to Helicobacter pylori. Gastroenterology. 2010;138:573–582. [PubMed]
62. Moran AP, Hynes SO, Heneghan MA. Mimicry of blood group antigen A by Helicobacter mustelae and H. pylori. Gastroenterology. 1999;116:504–505. [PubMed]
63. Monteiro MA, Appelmelk BJ, Rasko DA, Moran AP, Hynes SO, MacLean LL, et al. Lipopolysaccharide structures of Helicobacter pylori genomic strains 26695 and J99, mouse model H. pylori Sydney strain, H. pylori P466 carrying sialyl Lewis X, and H. pylori UA915 expressing Lewis B classification of H. pylori lipopolysaccharides into glycotype families. Eur J Biochem. 2000;267:305–320. [PubMed]
64. Monteiro MA, Chan KH, Rasko DA, Taylor DE, Zheng PY, Appelmelk BJ, et al. Simultaneous expression of type 1 and type 2 Lewis blood group antigens by Helicobacter pylori lipopolysaccharides. Molecular mimicry between H. pylori lipopolysaccharides and human gastric epithelial cell surface glycoforms. J Biol Chem. 1998;273:11533–11543. [PubMed]
65. Monteiro MA, Rasko D, Taylor DE, Perry MB. Glucosylated N-acetyllactosamine O-antigen chain in the lipopolysaccharide from Helicobacter pylori strain UA861. Glycobiology. 1998;8:107–112. [PubMed]
66. Heneghan MA, McCarthy CF, Moran AP. Relationship of blood group determinants on Helicobacter pylori lipopolysaccharide with host lewis phenotype and inflammatory response. Infect Immun. 2000;68:937–941. [PMC free article] [PubMed]
67. Simoons-Smit IM, Appelmelk BJ, Verboom T, Negrini R, Penner JL, Aspinall GO, et al. Typing of Helicobacter pylori with monoclonal antibodies against Lewis antigens in lipopolysaccharide. J Clin Microbiol. 1996;34:2196–2200. [PMC free article] [PubMed]
68. Wirth HP, Yang M, Peek RM, Jr, Hook-Nikanne J, Fried M, Blaser MJ. Phenotypic diversity in Lewis expression of Helicobacter pylori isolates from the same host. J Lab Clin Med. 1999;133:488–500. [PubMed]
69. Appelmelk BJ, Martin SL, Monteiro MA, Clayton CA, McColm AA, Zheng P, et al. Phase variation in Helicobacter pylori lipopolysaccharide due to changes in the lengths of poly(C) tracts in alpha3-fucosyltransferase genes. Infect Immun. 1999;67:5361–5366. [PMC free article] [PubMed]
70. Appelmelk BJ, Shiberu B, Trinks C, Tapsi N, Zheng PY, Verboom T, et al. Phase variation in Helicobacter pylori lipopolysaccharide. Infect Immun. 1998;66:70–76. [PMC free article] [PubMed]
71. Gibson JR, Chart H, Owen RJ. Intra-strain variation in expression of lipopolysaccharide by Helicobacter pylori. Lett Appl Microbiol. 1998;26:399–403. [PubMed]
72. Linden S, Boren T, Dubois A, Carlstedt I. Rhesus monkey gastric mucins: oligomeric structure, glycoforms and Helicobacter pylori binding. Biochem J. 2004;379:765–775. [PubMed]
73. Wirth HP, Yang M, Sanabria-Valentin E, Berg DE, Dubois A, Blaser MJ. Host Lewis phenotype-dependent Helicobacter pylori Lewis antigen expression in rhesus monkeys. Faseb J. 2006;20:1534–1536. [PMC free article] [PubMed]
74. Pohl MA, Romero-Gallo J, Guruge JL, Tse DB, Gordon JI, Blaser MJ. Host-dependent Lewis (Le) antigen expression in Helicobacter pylori cells recovered from Leb-transgenic mice. J Exp Med. 2009;206:3061–3072. [PMC free article] [PubMed]
75. Axsen WS, Styer CM, Solnick JV. Inhibition of heat shock protein expression by Helicobacter pylori. Microb Pathog. 2009;47:231–236. [PubMed]
76. Ozbek A, Ozbek E, Dursun H, Kalkan Y, Demirci T. Can Helicobacter pylori Invade Human Gastric Mucosa?: An In Vivo Study Using Electron Microscopy, Immunohistochemical Methods, and Real-time Polymerase Chain Reaction. J Clin Gastroenterol. 2009 Epub ahead of print. [PubMed]
77. Amieva MR, Salama NR, Tompkins LS, Falkow S. Helicobacter pylori enter and survive within multivesicular vacuoles of epithelial cells. Cell Microbiol. 2002;4:677–690. [PubMed]
78. Bjorkholm B, Zhukhovitsky V, Lofman C, Hulten K, Enroth H, Block M, et al. Helicobacter pylori entry into human gastric epithelial cells: A potential determinant of virulence, persistence, and treatment failures. Helicobacter. 2000;5:148–154. [PubMed]
79. Israel DA, Salama N, Arnold CN, Moss SF, Ando T, Wirth HP, et al. Helicobacter pylori strain-specific differences in genetic content, identified by microarray, influence host inflammatory responses. J Clin Invest. 2001;107:611–620. [PMC free article] [PubMed]
80. Salama NR, Gonzalez-Valencia G, Deatherage B, Aviles-Jimenez F, Atherton JC, Graham DY, et al. Genetic analysis of Helicobacter pylori strain populations colonizing the stomach at different times postinfection. J Bacteriol. 2007;189:3834–3845. [PMC free article] [PubMed]
81. Giannakis M, Backhed HK, Chen SL, Faith JJ, Wu M, Guruge JL, et al. Response of gastric epithelial progenitors to Helicobacter pylori isolates obtained from Swedish patients with chronic atrophic gastritis. J Biol Chem. 2009;284:30383–30394. [PMC free article] [PubMed]
82. Censini S, Lange C, Xiang Z, Crabtree JE, Ghiara P, Borodovsky M, et al. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci USA. 1996;93:14648–14653. [PubMed]
83. Tummuru MK, Cover TL, Blaser MJ. Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: evidence of linkage to cytotoxin production. Infect Immun. 1993;61:1799–1809. [PMC free article] [PubMed]
84. Covacci A, Censini S, Bugnoli M, Petracca R, Burroni D, Macchia G, et al. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci USA. 1993;90:5791–5795. [PubMed]
85. Torres J, Perez-Perez GI, Leal-Herrera Y, Munoz O. Infection with CagA+ Helicobacter pylori strains as a possible predictor of risk in the development of gastric adenocarcinoma in Mexico. Int J Cancer. 1998;78:298–300. [PubMed]
86. Queiroz DM, Mendes EN, Rocha GA, Oliveira AM, Oliveira CA, Magalhaes PP, et al. cagA-positive Helicobacter pylori and risk for developing gastric carcinoma in Brazil. Int J Cancer. 1998;78:135–139. [PubMed]
87. Rudi J, Kolb C, Maiwald M, Zuna I, von Herbay A, Galle PR, et al. Serum antibodies against Helicobacter pylori proteins VacA and CagA are associated with increased risk for gastric adenocarcinoma. Dig Dis Sci. 1997;42:1652–1659. [PubMed]
88. Parsonnet J, Friedman GD, Orentreich N, Vogelman H. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut. 1997;40:297–301. [PMC free article] [PubMed]
89. Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res. 1995;55:2111–2115. [PubMed]
90. Kuipers EJ, Perez-Perez GI, Meuwissen SG, Blaser MJ. Helicobacter pylori and atrophic gastritis: importance of the cagA status. J Natl Cancer Inst. 1995;87:1777–1780. [PubMed]
91. Crabtree JE, Taylor JD, Wyatt JI, Heatley RV, Shallcross TM, Tompkins DS, et al. Mucosal IgA recognition of Helicobacter pylori 120 kDa protein, peptic ulceration and gastric pathology. Lancet. 1991;338:332–335. [PubMed]
92. Peek RM, Jr, Miller GG, Tham KT, Perez-Perez GI, Zhao X, Atherton JC, et al. Heightened inflammatory response and cytokine expression in vivo to cagA+ Helicobacter pylori strains. Lab Invest. 1995;73:760–770. [PubMed]
93. Kwok T, Zabler D, Urman S, Rohde M, Hartig R, Wessler S, et al. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature. 2007;449:862–866. [PubMed]
94. Jimenez-Soto LF, Kutter S, Sewald X, Ertl C, Weiss E, Kapp U, et al. Helicobacter pylori type IV secretion apparatus exploits beta1 integrin in a novel RGD-independent manner. PLoS Pathog. 2009;5:1000684. [PMC free article] [PubMed]
95. Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science. 2000;287:1497–1500. [PubMed]
96. Selbach M, Moese S, Hauck CR, Meyer TF, Backert S. Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo. J Biol Chem. 2002;277:6775–6778. [PubMed]
97. Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science. 2002;295:683–686. [PubMed]
98. Yamazaki S, Yamakawa A, Ito Y, Ohtani M, Higashi H, Hatakeyama M, et al. The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa. J Infect Dis. 2003;187:334–337. [PubMed]
99. Azuma T, Yamakawa A, Yamazaki S, Fukuta K, Ohtani M, Ito Y, et al. Correlation between variation of the 3′ region of the cagA gene in Helicobacter pylori and disease outcome in Japan. J Infect Dis. 2002;186:1621–1630. [PubMed]
100. Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ, Covacci A. c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol. 2002;43:971–980. [PubMed]
101. Schneider N, Krishna U, Romero-Gallo J, Israel DA, Piazuelo MB, Camargo MC, et al. Role of Helicobacter pylori CagA molecular variations in induction of host phenotypes with carcinogenic potential. J Infect Dis. 2009;199:1218–1221. [PMC free article] [PubMed]
102. Argent RH, Kidd M, Owen RJ, Thomas RJ, Limb MC, Atherton JC. Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori. Gastroenterology. 2004;127:514–523. [PubMed]
103. Argent RH, Thomas RJ, Aviles-Jimenez F, Letley DP, Limb MC, El-Omar EM, et al. Toxigenic Helicobacter pylori infection precedes gastric hypochlorhydria in cancer relatives, and H. pylori virulence evolves in these families. Clin Cancer Res. 2008;14:2227–2235. [PubMed]
104. Rota CA, Pereira-Lima JC, Blaya C, Nardi NB. Consensus and variable region PCR analysis of Helicobacter pylori 3′ region of cagA gene in isolates from individuals with or without peptic ulcer. J Clin Microbiol. 2001;39:606–612. [PMC free article] [PubMed]
105. Yamaoka Y, Kodama T, Gutierrez O, Kim JG, Kashima K, Graham DY. Relationship between Helicobacter pylori iceA, cagA and vacA status and clinical outcome: studies in four different countries. J Clin Microbiol. 1999;37:2274–2279. [PMC free article] [PubMed]
106. Higashi H, Tsutsumi R, Fujita A, Yamazaki S, Asaka M, Azuma T, et al. Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc Natl Acad Sci USA. 2002;99:14428–14433. [PubMed]
107. Bronte-Tinkew DM, Terebiznik M, Franco A, Ang M, Ahn D, Mimuro H, et al. Helicobacter pylori cytotoxin-associated gene A activates the signal transducer and activator of transcription 3 pathway in vitro and in vivo. Cancer Res. 2009;69:632–639. [PMC free article] [PubMed]
108. Saadat I, Higashi H, Obuse C, Umeda M, Murata-Kamiya N, Saito Y, et al. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature. 2007;447:330–333. [PubMed]
109. Bagnoli F, Buti L, Tompkins L, Covacci A, Amieva MR. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc Natl Acad Sci USA. 2005;102:16339–16344. [PubMed]
110. Murata-Kamiya N, Kurashima Y, Teishikata Y, Yamahashi Y, Saito Y, Higashi H, et al. Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene. 2007;26:4617–4626. [PubMed]
111. Zeaiter Z, Huynh HQ, Kanyo R, Stein M. CagA of Helicobacter pylori alters the expression and cellular distribution of host proteins involved in cell signaling. FEMS Microbiol Lett. 2008;288:227–234. [PubMed]
112. Lu H, Murata-Kamiya N, Saito Y, Hatakeyama M. Role of partitioning-defective 1/microtubule affinity-regulating kinases in the morphogenetic activity of Helicobacter pylori CagA. J Biol Chem. 2009;284:23024–23036. [PMC free article] [PubMed]
113. Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol. 2004;5:1166–1174. [PubMed]
114. Nagy TA, Frey MR, Yan F, Israel DA, Polk DB, Peek RM., Jr Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling. J Infect Dis. 2009;199:641–651. [PMC free article] [PubMed]
115. Kaparakis M, Turnbull L, Carneiro L, Firth S, Coleman HA, Parkington HC, et al. Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells. Cell Microbiol. 2009;12:372–385. [PubMed]
116. Leunk RD, Johnson PT, David BC, Kraft WG, Morgan DR. Cytotoxic activity in broth-culture filtrates of Campylobacter pylori. J Med Microbiol. 1988;26:93–99. [PubMed]
117. Lupetti P, Heuser JE, Manetti R, Massari P, Lanzavecchia S, Bellon PL, et al. Oligomeric and subunit structure of the Helicobacter pylori vacuolating cytotoxin. J Cell Biol. 1996;133:801–807. [PMC free article] [PubMed]
118. Phadnis SH, Ilver D, Janzon L, Normark S, Westblom TU. Pathological significance and molecular characterization of the vacuolating toxin gene of Helicobacter pylori. Infect Immun. 1994;62:1557–1565. [PMC free article] [PubMed]
119. Schmitt W, Haas R. Genetic analysis of the Helicobacter pylori vacuolating cytotoxin: structural similarities with the IgA protease type of exported protein. Mol Microbiol. 1994;12:307–319. [PubMed]
120. Telford JL, Ghiara P, Dell'Orco M, Comanducci M, Burroni D, Bugnoli M, et al. Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J Exp Med. 1994;179:1653–1658. [PMC free article] [PubMed]
121. Cover TL, Tummuru MK, Cao P, Thompson SA, Blaser MJ. Divergence of genetic sequences for the vacuolating cytotoxin among Helicobacter pylori strains. J Biol Chem. 1994;269:10566–10573. [PubMed]
122. Rhead JL, Letley DP, Mohammadi M, Hussein N, Mohagheghi MA, Eshagh Hosseini M, et al. A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology. 2007;133:926–936. [PubMed]
123. Letley DP, Lastovica A, Louw JA, Hawkey CJ, Atherton JC. Allelic diversity of the Helicobacter pylori vacuolating cytotoxin gene in South Africa: rarity of the vacA s1a genotype and natural occurrence of an s2/m1 allele. J Clin Microbiol. 1999;37:1203–1205. [PMC free article] [PubMed]
124. Atherton JC, Cao P, Peek RM, Jr, Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem. 1995;270:17771–17777. [PubMed]
125. Czajkowsky DM, Iwamoto H, Cover TL, Shao Z. The vacuolating toxin from Helicobacter pylori forms hexameric pores in lipid bilayers at low pH. Proc Natl Acad Sci USA. 1999;96:2001–2006. [PubMed]
126. Cover TL, Blanke SR. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol. 2005;3:320–332. [PubMed]
127. Iwamoto H, Czajkowsky DM, Cover TL, Szabo G, Shao Z. VacA from Helicobacter pylori: a hexameric chloride channel. FEBS Lett. 1999;450:101–104. [PubMed]
128. Tombola F, Carlesso C, Szabo I, de Bernard M, Reyrat JM, Telford JL, et al. Helicobacter pylori vacuolating toxin forms anion-selective channels in planar lipid bilayers: possible implications for the mechanism of cellular vacuolation. Biophys J. 1999;76:1401–1409. [PubMed]
129. Szabo I, Brutsche S, Tombola F, Moschioni M, Satin B, Telford JL, et al. Formation of anion-selective channels in the cell plasma membrane by the toxin VacA of Helicobacter pylori is required for its biological activity. EMBO J. 1999;18:5517–5527. [PubMed]
130. Cover TL, Vaughn SG, Cao P, Blaser MJ. Potentiation of Helicobacter pylori vacuolating toxin activity by nicotine and other weak bases. J Infect Diseases. 1992;166:1073–1078. [PubMed]
131. Li Y, Wandinger-Ness A, Goldenring JR, Cover TL. Clustering and redistribution of late endocytic compartments in response to Helicobacter pylori vacuolating toxin. Mol Biol Cell. 2004;15:1946–1959. [PMC free article] [PubMed]
132. Rieder G, Fischer W, Haas R. Interaction of Helicobacter pylori with host cells: function of secreted and translocated molecules. Curr Opin Microbiol. 2005;8:67–73. [PubMed]
133. Hotchin NA, Cover TL, Akhtar N. Cell vacuolation induced by the VacA cytotoxin of Helicobacter pylori is regulated by the Rac1 GTPase. J Biol Chem. 2000;275:14009–14012. [PubMed]
134. Papini E, Satin B, Bucci C, de Bernard M, Telford JL, Manetti R, et al. The small GTP binding protein rab7 is essential for cellular vacuolation induced by Helicobacter pylori cytotoxin. EMBO J. 1997;16:15–24. [PubMed]
135. Papini E, de BM, Bugnoli M, Milia E, Rappuoli R, Montecucco C. Cell vacuolization induced by Helicobacter pylori: inhibition by bafilomycins A1, B1, C1 and D. FEMS Microbiology Letters. 1993;113:155–159. [PubMed]
136. Molinari M, Salio M, Galli C, Norais N, Rappuoli R, Lanzavecchia A, et al. Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA. J Exp Med. 1998;187:135–140. [PMC free article] [PubMed]
137. Satin B, Norais N, Telford J, Rappuoli R, Murgia M, Montecucco C, et al. Effect of Helicobacter pylori vacuolating toxin on maturation and extracellular release of procathepsin D and on epidermal growth factor degradation. J Biol Chem. 1997;272:25022–25028. [PubMed]
138. Willhite DC, Cover TL, Blanke SR. Cellular vacuolation and mitochondrial cytochrome c release are independent outcomes of Helicobacter pylori vacuolating cytotoxin activity that are each dependent on membrane channel formation. J Biol Chem. 2003;278:48204–48209. [PubMed]
139. Kimura M, Goto S, Wada A, Yahiro K, Niidome T, Hatakeyama T, et al. Vacuolating cytotoxin purified from Helicobacter pylori causes mitochondrial damage in human gastric cells. Microb Pathog. 1999;26:45–52. [PubMed]
140. Galmiche A, Rassow J, Doye A, Cagnol S, Chambard JC, Contamin S, et al. The N-terminal 34 kDa fragment of Helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release. EMBO J. 2000;19:6361–6370. [PubMed]
141. Yamasaki E, Wada A, Kumatori A, Nakagawa I, Funao J, Nakayama M, et al. Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic proteins Bax and Bak, leading to cytochrome c release and cell death, independent of vacuolation. J Biol Chem. 2006;281:11250–11259. [PubMed]
142. Cover TL, Krishna US, Israel DA, Peek RM., Jr Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin. Cancer Res. 2003;63:951–957. [PubMed]
143. Kuck D, Kolmerer B, Iking-Konert C, Krammer PH, Stremmel W, Rudi J. Vacuolating cytotoxin of Helicobacter pylori induces apoptosis in the human gastric epithelial cell line AGS. Infect Immun. 2001;69:5080–5087. [PMC free article] [PubMed]
144. Oldani A, Cormont M, Hofman V, Chiozzi V, Oregioni O, Canonici A, et al. Helicobacter pylori counteracts the apoptotic action of its VacA toxin by injecting the CagA protein into gastric epithelial cells. PLoS Pathog. 2009;5:1000603. [PMC free article] [PubMed]
145. Mimuro H, Suzuki T, Nagai S, Rieder G, Suzuki M, Nagai T, et al. Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach. Cell Host Microbe. 2007;2:250–263. [PubMed]
146. Zheng PY, Jones NL. Helicobacter pylori strains expressing the vacuolating cytotoxin interrupt phagosome maturation in macrophages by recruiting and retaining TACO (coronin 1) protein. Cell Microbiol. 2003;5:25–40. [PubMed]
147. Allen LA, Schlesinger LS, Kang B. Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages. J Exp Med. 2000;191:115–128. [PMC free article] [PubMed]
148. Rittig MG, Shaw B, Letley DP, Thomas RJ, Argent RH, Atherton JC. Helicobacter pylori-induced homotypic phagosome fusion in human monocytes is independent of the bacterial vacA and cag status. Cell Microbiol. 2003;5:887–899. [PubMed]
149. Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, et al. The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J Exp Med. 2003;198:1887–1897. [PMC free article] [PubMed]
150. Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R. Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science. 2003;301:1099–1102. [PubMed]
151. Sundrud MS, Torres VJ, Unutmaz D, Cover TL. Inhibition of primary human T cell proliferation by Helicobacter pylori vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion. Proc Natl Acad Sci USA. 2004;101:7727–7732. [PubMed]

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