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    Pa Tho Genesis of Helicobacter Pylori Infection

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    Roberto Cjuno Chacca

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    Attribution Non-Commercial (BY-NC)
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    Helicobacter ISSN 1523-5978 Pathogenesis of Helicobacter pylori Infection ‘Ana C. Costa,*' Ceu Figueiredo* and Eliette Touati! “PATMUP «Insitute of Walesa Porto, Ports, Perugal ‘Unis de Keywords Hose cela vee aga, signaling, carnogeness,srimirobal epee requests to: Ele Tous, unt de Pathogentee de Heicobactr, stu Paste 28 Rue du Doct Rous, 75015 Pars, France mal etoue@pasteucie athology and rmmunclogy ofthe Unversity af Por, Porto, Portugal, "Medea Faculty of he University of openése de Helcobactr, nstut Pasteur, Pais, France Abstract, Helicobacter pylori induces chronic inflammation of the gastric mucosa, but only a proportion of infected individuals develop peptic ulcer disease or gas- ic carcinoma. Reasons underlying these observations include differences in bacterial pathogenicity as well as in host susceptibility. Numerous studies published in the last year provided new insight into H, pylori virulence fac- tors, their interaction with the host and consequences in pathogenesis, These include the role of bacterial genetic diversity in host colonization and persistence, outer membrane proteins and modulation of adhesin expres sion, new aspects of VacA functions, and CagA and its phosphorylation- dependent and -independent cellular effects. This ar recent novel findings on the interactions of H. pylori with diverse host epi- thelial signaling pathways and events involved in the initlation of carcino. Je will also review the genesis, including genetic instability and dysregul Helicobacter pylori Virulence Factors Helicobacter pylori Genetic Diversity and Host Colonization Helicobacter pylori is characterized by a high level of genetic diversity which can be important for the adap- tation to the host stomach and for the clinical outcome of the infection. Differences in gene content among pylori isolates in Mexican patients with various gastric pathologies, including cancer, showed patterns of dis- cease-associated genes [1] ‘The plasticity of the H. pylori genome derives from its natural competence for transformation by exogenous DNA, from recombination and properties are at the origin of an extensive allelic diver- sity occurring even in a single host. Insertion of chro- ‘mosomal DNA fragments of 1300 bp length into the recipient chromosome, associated with active genetic recombination, was demonstrated [2]. During homolo- gous recombination, Holliday junctions generated by the RecG and RuvAB helicases are resolved by Ruv¢ The RecG homolog of H. pyler is devoid of resalvase activity and provides an anti-repair pathway [3]. It was suggested that competition between repair and anti- repair pathways may provide a mechanism to generate strain diversity and to maximize fitness at the bacterial population level [3]. 1m mutations, These Alter natural transformation of 19 of DNA repait 1. pylori, the import of short DNA fragments (1294 to 3853 bp) interrupted by interspersed sequences of the recipient (ISR) (mean length of 82 bp) was shown to result in the formation of complex mosaic alleles [4] ‘The control of import length and initiation of the ISR formation was dependent on the DNA. glycosylase Mut¥, a component of the base excision repair (BER) pathway, In vivo, H. pylori is exposed to acidity and oxidative stress, causing bacterial DNA damage. AddAB have both nuclease and helicase activities similar to RecRCD. AddA (HP1553) confers 1 induced DNA damage. addA mutants display a signifi- cantly reduced DNA recombination frequency. In mice, AUAB and RecA are required for stomach colonization {5}. Thet gene conversion-like events, a mechanism selected in the host that abolishes BabA-dependent adherence (6] These data are in support of DNA repair and recombi pation as essential H. pylori mechanisms to optimize bacterial adherence to mucosal epithelium and persis tent colonization, lance to oxidative stress le in bacterial adherence is associated with Outer Membrane Proteins and Adherence ‘The # pylori genome contains about 40 hop gene paral- ogous encoding outer membrane (om), Mutations in hopQ increased adherence of H. pylori to proteins 8 1H. Pylon Pathogenesis AGS gastric epithelial cells, CagA translocation into host cells and cellular alterations, demonstrating the impor- tance of HopQ for bacterial adherence [7]. The hopQ lype I genotype was associated with higher atrophy scores than the type If genotype and was proposed as a ‘marker for gastroduodenal diseases [8] Expression of adhesins might be modulated by genetic changes, Phase variation via slipped-strand iispairing in repetitive nucleotide tracts modulate sabA. ‘expression, Goodwin et al. (9] reported that suBA alleles of multiple length in the polyT and CT repeat tracts rear the s4bAB 5° end, ate found in 25% of clones of strain 26695, This was also confirmed among multiple H. pylor isolates from a single patient [9]. This mecha- rnism occurring during chromosomal replication sug- gests a selective pressure for SabA expression in the host, allowing bacteria to adapt but also to escape host immune response. In the same study, transcription of sabA. was repressed by the acid-responsive ArsRS two- ‘component signal transduction (TCST) system in vitro [9]. BabA and SabA bind 10 the Lewis B (Le!) and to slycosphingolipids displaying a sialyl-dimeric Lewis X (sialyl-Le) respectively. In young mice with early ‘acquisition of H. pylori infection, a higher slalyl-Le* was correlated with persistence of stomach colonization {10}. A cag pathogenicity island (PAI)-dependent over- ‘expression of a GIeNAc transferase (b3GnTS) was described in gastric carcinoma cell lines and associated ‘with high #1. pylor’ adherence [11], Four binding modes for the #. pylori-mucin interac- ton are likely to play roles in various niches along the ‘orogastric infection route and vary according to pH, gastritis status and bacterial strain [12]. Glycoprotein receptors within the human salivary proteome for the carbohydrate-hinding # pylori adhesins have been also identified [13]. Binding of 1. pylori to salivary mucin MUCT and agglutinin gp340 depended exclusively on SabA and BabA, respectively. Binding to MUCSB was mainly due to BabA. SabA was also found to bind the secretory component of the polymeric Ig receptor (SC) and Igs-chain (S-IgA-He). These interactions can modu- late surface or adhesive properties of the bacteria along the digestive tract, In gastric precancerous lesions and. in gastric carcinoma, the expression of MUCSAC and 'MUC6 Is altered. Using the Rhesus macague model, Cooke et al, investigated the effects on gastric mucins of experimental challenge with H pylori during acute and chronic infection [14]. Hf pylori induced gastritis with an acute and high transient decrease in diversity and low relative abundance of O-linked raucin oligosac- charides, suggesting that bacteria modulate gastric mucin glycoproteins during acute infection to promote ‘colonization and persistent infection. costae a. Trefoil factors are involved in repair of the gastroin. testinal mucosa, MUCSAC is coexpressed with trefoil factor family (TFF)1, a member of small cysteine-rich proteins. Reeves et al. [15] showed binding of the core oligosaccharide portion (rough form) of #1. pylori lipo polysaccharide (RF-LPS) to TEPI, at an optimum pH of 5-6, An increase in pll would cause inappropriate bind: ing of bacteria close to the lumen, leading to removal by mucus turnover. In patients with active chronic gas- titis, a reduced expression of TFF2 was observed, espe cially in those patients infected with CagA-positive strains, Authors propose that this reduction in expres sion could contribute to the damage induced to the gas tric mucosa by HE. pylon [16] ‘The cytotoxin Vaca Vaca is an important virulence factor in the pathogene sis of peptic ulceration and gastric cancer. This toxin can induce multiple cellular activities, including cell vacuolation, membrane channel formation, disruption of endosomal/Iysosomal function, apoptosis, and immu nomodulation. The mature monomeric form of Vac hhas 2 domains - p55 and p33 - important for its cellular activity. Ivie et al. [17] showed that the N-terminal of p95 is essential for VacA-induced vacuolation and for hhost cell membrane depolarization. This domain is Important for the formation of VacA oligomeric struc: tures, suggesting its role in the formation of anjonic ‘membrane channels. Further insight into the final steps of vacuole formation by Vac was provided by Mashi ma ctal. [18], by demonstrating that the vesicle associated membrane protein 7 (VAMP?) is a partner of (Q-SNARE syntaxin 7 in the process of lysosome-endo- some fusion. ‘At the nucleotide level, the vacA intermediate (i) region, which encodes part of the p33. Vac subunit, displays sequence variation, I-type strains were associ ated with gastric carcinoma in an Iranian population [19], and were an independent predictor of peptie ulcer disease in an Italian population {20} In addition to the previously described protein tyro. sine phosphatase receptor (RPTP)-x and RPTP-f, Gupta et al [21] identified sphingomyelin (SM) as a host cell receptor for Vaca, SM was essential for VacA associa tion with the cell membrane and for toxin-induced vac- uuolation, VacA binding to specialized membrane functional domains may have a biological meaning in cell signaling. Tegimeyer et al. [22] showed that VacA can inhibit some Caga-induced responses on epithelial cells. Vac inhibited the activation of epidermal growth factor receptor (EGFR) and HER2/Neu, and subsequently Juma complter © 200 suctwel ising, leeabice 1 Sipl 1529, costae a ErkI/2 MAP kinase, which are important for cell scat- tering and elongation. These results are also in agree- ‘ment with previous findings suggesting that VacA and Cag downregulate each other's effects on epithelial cells, potentially allowing H. pylori interaction with cells whilst avoiding excessive cellular damage [23] ‘A novel mechanism underlying IL pylori-induced Inhibition of acid secretion by parietal cells was pro- posed by Wang et al. [24]. They showed that Vach Imteraction with parictal cells promotes calpain-medi- ated proteolysis of ezrin, disrupting the apical mem- brane-cytoskeletal interactions and inhibiting gastric acid secretion, mimicking the hypochlorhydric pheno- type observed in H. pylorintected patients, Tuo et al. [25] demonstrated that Vac inhibits pros- taglandin F2-stimulated duodenal mucosal bicarbonate secretion by stimulating the release of mucosal hista- ‘mine. These findings may have pathophysiologic rele- the inhibitory of Vacd bicarbonate secretion may impair duodenal mucosal defense against acid injury, contributing to ulcer development vance since cftect on The cag Pathogenicity Island and cagA The cagPAI is a genomic region of 40 Kb containing about 30 genes encoding @ type IV secretion system (T45S}. To gain more insight into the role of the T4SS fon the outcome of gastric disease, Wiedemann etal used the Mongolian gerbil model in a long-term infec- sion experiment (2-64 weeks) [26]. Authors showed that the T4SS is essential for the induction of an early and severe corpus inflammation, associated with inereased expression of proinflammatory cytokines and histopathologic changes such as atrophic gastritis and metaplasia. At late time points, only animals infected with T48S-competent bacteria developed hypochlorhy- dria and hypergastrinemia in parallel to gastric ulcers and focal dysplasia. Although gastric adenocarcinoma was not detected in any of the infected animals, they show that the Mongolian gerbil model parallels the multistep process of gastric carcinogenesis that occurs in humans. ‘The cagPAL-encoded factor Cagh was investigated and lis crystal structure was determined [27]. In contradic- tion with previous findings [28], Cagb was identified as Aan essential component of the TASS that is required for CagA translocation into host epithelial cells, although not absolutely necessary for pilus assembly. aga, also encoded by the

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