Helicobacter ISSN 1523-5378

Torresncompilation Ltd Infection Publishing Ltd, Helicobacter XX: xxxx Pathogenesis of l e pylori O r2008andA r t i cH. s 2008 Blackwell XXX Journal i gi UK 1523-5378 1083-4389 Helicobacter HEL a Authors Oxford, The Backert Blackwelll Publishing

Pathogenesis of Helicobacter pylori Infection

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Javier Torres* and Steffen Backert

Unidad de Investigacion en Enfermedades Infecciosas, UMAE Pediatria, IMSS, Mexico, Department of Medical Microbiology, Otto von Guericke University, D-39120 Magdeburg, Leipziger Str. 44, Germany

Keywords Helicobacter pylori, signaling, cancer, type IV secretion system, vacuolating cytotoxin. Reprint requests to: Steffen Backert, Department of Medical Microbiology, Otto von Guericke University, D-39120 Magdeburg, Leipziger Str. 44, Germany. E-mail: steffen.backert@med.ovgu.de

Abstract The clinical outcome of Helicobacter pylori infection is determined by a complex scenario of interactions between the bacterium and the host. The main bacterial factors associated with colonization and pathogenicity comprise outer membrane proteins including BabA, SabA, OipA, AlpA/B, as well as the virulence factors CagA in the cag pathogenicity island (cagPAI) and the vacuolating cytotoxin VacA. The multitude of these proteins and allelic variation makes it extremely difcult to test the contribution of each individual factor. Much effort has been put into identifying the mechanism associated with H. pylori-associated carcinogenesis. Interaction between bacterial factors such as CagA and host signal transduction pathways seems to be critical for mediating the induction of membrane dynamics, actin-cytoskeletal rearrangements and the disruption of cell-to-cell junctions as well as proliferative, pro-inammatory and antiapoptotic nuclear responses. An animal model using the Mongolian gerbil is a useful system to study the gastric pathology of H. pylori infection.

H. pylori Colonization, Adherence, and Tissue Damage in Humans

Bacterial Factors
During the last year, important contributions have been made on bacterial genes involved in the complex processes of colonization and persistence of Helicobacter pylori in the gastric mucosa. A new approach based on the use of transposon mutant libraries and whole-genome microarrays in an animal model allowed the identication of genes involved in colonization in humans [1]. The study identied known genes involved in motility, chemotaxis, and urease activity, but it also revealed novel factors such as ketoglutarate permease, UDP-glucose4-epimerase, and genes with unknown functions. Comparison of the H. pylori in vivo to the in vitro transcriptome at pH 7.4 showed that almost all known acid acclimation genes are highly upregulated. These include ureA/B, rocF, and the pH-gated urea channel, ureI [2]. New information concerning the participation of outer membrane proteins (OMPs) in bacterial adherence was also reported. Deletion of alpA/B genes reduced binding of H. pylori and colonization of stomachs in mice [3]. This study also showed that alpA/B-negative East Asian but not Western strains induced less interleukin-8 (IL-8) release from human cells than alpA/B-positive strains. The protein

encoded by horB is another member of the family of OMPs whose inactivation caused a reduced bacterial colonization of the gastric mucosa, as well as a decrease in the expression of LPS O-chain and of Lewis antigens in mice [4]. Similarly, knockout of the tip- gene caused a decrease in the ability of H. pylori to colonize the gastric mouse mucosa, and Tip- also induced the release of pro-inammatory mediators such as IL-1 and tumor necrosis factor (TNF). A variety of other factors also have an important role in bacterial colonization. The participation of - and -carbonic anhydrases of H. pylori in pH homeostasis is known. A recent study demonstrated that mutation in either enzyme signicantly reduced the ability of strains to colonize the murine gastric mucosa, although the effect varied among different strains [5]. Mutation of - and -carbonic anhydrases also reduced the inammation score in the colonized gastric mucosa. A number of virulence properties have been assigned to the CagA effector protein. In terms of colonization, H. pylori suppressed apoptosis of gastric epithelial cells in the Mongolian gerbil model and enhanced cell survival, thus favoring persistent colonization [6]. The study demonstrates that CagA increases expression of the antiapoptotic protein MCL1 via the MekErkSRE pathway. The oipA gene has also been suggested to have a role in H. pylori colonization by functioning as an adhesin. In a recent work, Franco et al. demonstrated that oipA-negative strains

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had a decreased ability to induce gastric cancer in gerbils [7]. They also showed that H. pylori strains isolated from human patients with precancerous lesions expressed OipA in signicantly higher amounts [7]. It has also been shown that the recN gene, besides its role in recombinational DNA repair, participates in colonization and survival in vivo in a rodent model, probably by helping the bacteria to better respond to oxidative stress conditions [8].

Host Factors
The host mucosal environment exhibits an important and dynamic role in the response to the presence of H. pylori infection; this is particularly true for glycoconjugates. H. pylori has developed the ability to adhere to different host receptors. BabA binds fucosylated blood group antigens, whereas SabA binds sialylated Lewis antigens. A recent study reported the dynamics of mucosal glycosylation in response to H. pylori infection and conrmed previous work showing modulation in the expression of adhesins in response to changes in the host mucosa [9]. Thus, in the early stages of colonization, BabA binds to fucosylated blood group antigens; however, the initial colonization induces inammation and increases the expression of sialylated mucosal antigens with concurrent decrease in fucosylated antigens. H. pylori responds to these changes by expression of the SabA adhesin which has afnity for sialylated blood group antigens. On the other hand, gastric adenocarcinoma has been linked to the muc1 genotype; short muc1 alleles have been associated with Helicobacter-induced gastritis and gastric adenocarcinoma. The impact of Muc1 expression on the colonization and pathogenesis of H. pylori infection has been studied [10]. Muc1() mice were signicantly more colonized than wild-type mice and developed a more severe atrophic gastritis. This study conrmed that Muc1 offers a protective barrier which limits H. pylori colonization.

polymorphisms within genes such as vacA or babA. It has recently been suggested that in the case of the CagA, the number of EPIYA-motifs in the 3 region correlates with levels of tyrosine-phosphorylation, SHP2-binding activity, and risk for disease; thus, a higher number of EPIYA-C motifs were associated with stronger cell damage and more severe disease. This seems to be not always the case, and strains with the same pattern of EPIYA-motifs were reported to have a wide heterogeneous activity on gastric epithelial cells [12]. This study also documented a signicant diversity in the biologic activity among strains isolated from a single patient.

In the Host
The innate immune system plays an important role in the outcome of H. pylori infection. Reports on cancer (other than in the stomach) have demonstrated the importance of Toll-like receptors (TLRs) in the progression and severity of cancer. A population-based casecontrol study found that a TLR4 +896A > G polymorphism is a risk factor for noncardia gastric carcinoma, whereas in relatives of gastric cancer patients, carriers of TLR4 +896G had a 11-fold increased odds ratio for hypochlorhydria and more severe gastric atrophy and inammation [13]. Thus, a polymorphism that impairs reactivity to bacterial lipopolysaccharide (LPS) may play a role in gastric carcinogenesis. Polymorphisms in interleukins have also been reported to be associated with the development of gastric cancer; in a study of 207 polymorphisms of 11 cytokine genes in Japanese gastric cancer patients and dyspeptic control patients, IL-4 gene diplotypes (984 and 2983 AA/GA) had a negative association with the risk of developing gastric cancer [14].

Other In Vivo and In Vitro Models of H. pylori Pathogenesis

In vitro cell culture models have been widely used to study the H. pylori host cell interaction in different cell types. A recent study reported that AGS gastric epithelial cells infected with a cagPAI-positive strain resulted in a higher frequency of nucleotide alterations in TP53, suggesting that H. pylori promotes somatic mutation [15]. They demonstrated that this effect was associated with an aberrant expression of activation-induced cytidine deaminase, which acts as a DNA- and RNA-editing enzyme. Using AGS cells, the effect of H. pylori infection on the expression of epidermal growth factor receptor (EGFR) was studied. EGFR has promitotic and antiapoptotic properties and its overexpression may lead to uncontrolled proliferation and to increased risk of gastric neoplasia. It was found that infection with cagPAI-positive strains lead to a signicant increase in the expression of EGFR by a mechanism which

Genetic Diversity and Pathogenesis

In H. pylori
It has been argued that the striking genetic variability observed in H. pylori strains contributes to host adaptation and persistent colonization. Genetic diversity has been observed even between strains infecting an individual host; and the question remains open whether this diversity represents diversication of one strain or mixed infections. A recent study reports that humans are infected with a population of closely related strains that vary at a small number of gene loci [11]. This suggests that the observed diversity in strains within a host is due to a mixed infection and not due to diversication of a single strain. Diversity is not limited to gene content but also to known

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Pathogenesis of H. pylori Infection

involves EGFR transactivation, Erk phosphorylation, and Src activation [16]. MKN28 and MKN45 cell models have also provided novel insights. For example, CagA interacts with E-cadherin, thus destabilizing its complex with catenin, resulting in nuclear accumulation of -catenin. Nuclear -catenin transactivates genes such as cdx1, encoding an intestinal specic transcription factor, and p21 that causes G1 cell-cycle arrest [17]. By activating -catenindependent genes that are involved in intestinal type differentiation, CagA may play a role in the transdifferentiation of gastric mucosa to an intestinal type, as observed in intestinal metaplasia [17]. The activity of H. pylori may vary in different cell types. When human MCF-7 breast cancer cells were studied, it was found that junction complexes were disrupted independently of CagA [18]. The latter effect seems to be mediated by cleavage of the extracellular domain of E-cadherin by a yet unknown secretory product. Finally, the group of Hatakeyama constructed transgenic mice expressing CagA, which developed gastric polyps and adenocarcinomas of the stomach and small intestine in the absence of H. pylori [19]. Systemic expression of CagA further induced leukocytosis with IL-3/G-CSF hypersensitivity, and some mice developed myeloid leukemias and Bcell lymphomas. These results provide rst direct evidence for CagA as a bacterium-derived oncoprotein in humans.

number of bacteria get access to integrins and can inject CagA. In line with this hypothesis, inactivation of oipA also had an effect on FAK activity [21]. The importance of 1-integrin for H. pylori-induced host cell motility and elongation was also reported [20,22], and this signaling is associated with the phosphorylation of paxillin and the MAP-kinase JNK [22]. Two other cagPAI-encoded factors, Cag and CagF, have also been investigated recently. The crystal structure of Cag shows a hexameric ring in complex with the regulator protein HP1451 and functions as a gating molecule for delivery of CagA at the inner bacterial membrane [23]. CagF is a chaperone-like protein that interacts with a 100amino-acid region that is adjacent to the C-terminal secretion signal of CagA [24]. Interestingly, the interaction between CagA and CagF takes place at the bacterial cytoplasmic membrane, and is independent of a functional T4SS.

VacA
The pore-forming toxin VacA exerts different effects on both epithelial and immune cells. CD2-associated protein (CD2AP), a docking protein implicated in intracellular trafcking, bridged lamentous actin (F-actin) with early endosomes containing VacA [25]. CD2AP regulated the F-actin structures and was required to transfer VacA from early to late endosomes. These results demonstrate that sorting of VacA in these compartments requires dynamic F-actin structures on early endosomes [25]. Swelling of these endosomes into vacuoles is caused by concerted interactions with the v-ATPase proton pump [26]. Another milestone is that the crystal structure of the putative receptor-binding domain of VacA (p55) has been solved. It consists of a parallel -helix with a carboxy-terminal globular domain [27]. Analysis of VacA sequences from unrelated H. pylori strains, including m1/m2-alleles, allowed identication of structural features of the VacA surface that may be important for interactions with host receptors. Modeling of VacA showed how p55 monomers may assemble into oligomers capable of membrane pore formation [27].

Bacterial Virulence Factors

cag Pathogenicity Island
The cagPAI encodes a type IV secretion system (T4SS) for the delivery of CagA. For a long time it was believed that CagA can be randomly injected into epithelial cells. This is obviously not the case because a recent study showed that integrin receptors are required for injection of CagA [20]. An important role is played by CagL, a T4SS-pilus-covering protein, which acts as a specialized adhesin bridging the T4SS to 1-integrin on target cells [20]. In addition, it was found that CagL activates the host kinases FAK and Src to ensure phosphorylation of CagA directly at the injection site. This was the rst study showing directly that a bacterial T4SS-protein targets a host receptor for its function. Interestingly, integrins are not found at the apical membrane but at the basal membrane of polarized cells facing away from the lumen. This suggests a sophisticated mechanism controlling how H. pylori injects CagA [20]. The basal injection model of CagA can also explain why H. pylori does not cause much more damage in the gastric epithelium. A likely scenario might be that cagPAIindependent factors such as the known adhesins BabA/B, SabA, AlpA/B as well as VacA and OipA loosen the intercellular epithelial junctions locally before a limited

Signal Transduction Pathways in Epithelial Cells Induced by H. pylori

Tyrosine-phosphorylation is an important event to activate injected CagA [28]. Besides Src, Abl kinases (c-Abl and Arg) were also identied to directly phosphorylate the EPIYAmotifs in CagA [29,30]. H. pylori controls the activity of Src and Abl in a very specic and time-dependent manner. A model for the successive phosphorylation of CagA (CagAPY) by Src and Abl was proposed [29]. CagAPY interacts with

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multiple host cell proteins to induce downstream signals potentially involved in numerous phenotypic responses. For example, CagAPY binds the adapter protein CrkII as well as Abl, which phosphorylates CrkII in this complex to stimulate downstream signaling cascades such as that of Rac1 GTPase which triggers host cell motility [29,31]. Another novel target of CagAPY-signaling is the focal adhesion protein vinculin. The CagAPYCskSrc pathway modies the tyrosine-phosphorylation status of vinculin, resulting in a reduced number of focal adhesion complexes [32]. The latter implies two effects: 1, loss of cell adhesion to the extracellular matrix and 2, deregulation of focal adhesion turnover contributing to cell elongation. Injected CagA can also induce downstream signaling in a phosphorylation-independent manner. One of the novel targets of nonphosphorylated CagA is matrix metalloproteinase-1 (MMP-1) secretion induced by the CagAErkMMP-1 pathway [33]. As mentioned above, it was shown that CagA binds to E-cadherin and destabilizes the E-cadherin/-catenin complex [17]. Mutagenesis of Western and East Asian CagA variants revealed that deregulation of -catenin is mediated by a 16-amino-acid multimerization sequence at the carboxy-terminus of CagA [34]. Finally, CagA was shown to specically interact with PAR1/MARK kinase, which has an essential role in epithelial cell polarity [35]. Association of CagA inhibits PAR1 kinase activity and prevents atypical protein kinase C (aPKC)-mediated PAR1 phosphorylation, which dissociates PAR1 from the membrane, collectively causing junctional and polarity defects. Taken together these molecular mechanisms appear to be important for CagAinduced cell scattering.

CD4(+) T cells, CD8(+) T cells, and B cells. VacA also inhibited the proliferation of puried primary human CD4(+) T cells that were stimulated by dendritic cells. VacA inhibited both T-cell-induced and PMA/anti-IgM-induced proliferation of puried B cells. Thus, the immunomodulatory actions of VacA on T and B lymphocytes, the major effectors of the adaptive immune response, may contribute to the ability of H. pylori to establish a persistent infection in the human gastric mucosa. Second, GGT was identied as a novel factor involved in inhibition of T-cell proliferation [38]. Recombinant GGT exhibited antiproliferative activity. Cell-cycle analysis of human T cells indicated that GGT was necessary and sufcient to induce G(1) arrest. Reduced levels of c-Myc and phosphorylated c-Raf kinase suggest the disruption of Ras-dependent signaling by GGT. Thus, GGT is a novel immunosuppressive factor of H. pylori inhibiting T-cell proliferation by induction of a cell-cycle arrest in the G(1) phase.

Conicts of interest
The authors have declared no conicts of interest.

References
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Signal Transduction Pathways in Immune Cells Induced by H. pylori

Infection with H. pylori can last lifelong, but reasons for this persistence are not fully understood. There are several new reports showing that VacA and GGT (-glutamyl transpeptidase) play a crucial role in this context. First, VacA exhibits immunosuppressive effects, inhibiting IL-2 secretion by interference with the T-cell receptor/IL-2 signaling pathway at the level of calcineurin, the Ca2+calmodulin-dependent phosphatase. To achieve this, VacA efciently enters human T lymphocytes by binding to the 2-integrin receptor (CD18) and exploiting the recycling of lymphocyte function-associated antigen (LFA)-1 [36]. VacA targeted human, but not murine, CD18 for cell entry, consistent with the species-specic adaptation of H. pylori. Furthermore, VacA inhibits the proliferation of various other types of primary human immune cells [37]. Intoxication of peripheral blood mononuclear cells with VacA inhibited the stimulation-induced proliferation of

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