γ-Glutamyltranspeptidase of Helicobacter pylori induces mitochondria-mediated apoptosis in AGS cells

Kim, Kyungmi; Lee, Seung-Gyu; Park, Min-Gyu; Song, Jea-Young; Kang, Hyung-Lyun; Lee, Woo‐Kon; Cho, Myung-Je; Rhee, Kwang‐Ho; Youn, Hee‐Shang; Baik, Seung‐Chul

doi:10.1016/j.bbrc.2007.02.021

Cited by 58 publications

(41 citation statements)

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“…Three genes, including flaB (37), HP1192, and cheY (41), encode motilityand chemotaxis-related proteins; the flaB gene and HP1192 were upregulated about threefold. Three genes, HP0175, cagA, and gtt, encode apoptosis-related proteins (5,23,30,39). Results showed some operons involved and some genes are monocistronically transcribed genes ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

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The 3′-to-5′ Exoribonuclease (Encoded by HP1248) ofHelicobacter pyloriRegulates Motility and Apoptosis-Inducing Genes

et al. 2009

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The human gastric pathogen Helicobacter pylori has many virulence factors involved in pathogenesis, but the mechanisms regulating these virulence factors are not yet fully understood. In this study, we cloned HP1248, which is similar in sequence to Escherichia coli vacB, which was previously shown to be associated with the expression of virulence in Shigella and enteroinvasive E. coli. E. coli vacB encodes RNase R. RNase R is involved in the posttranscriptional regulation of mRNA stability. By global transcriptional microarray profiling of an H. pylori HP1248 deletion mutant, we defined six virulence-related genes which were posttranscriptionally downregulated by HP1248, including the motility-related genes HP1192 and flaB, the chemotaxis-related gene cheY, and the apoptosis-inducing genes HP0175, cagA, and gtt. In this study, recombinant HP1248 protein expressed in E. coli showed 3-to-5 exoribonuclease activity. Motility and apoptosis induction were increased in the H. pylori HP1248 deletion mutant. We also showed that HP1192 is associated with H. pylori motility, possibly through HP1248 regulation. Further, we suggested and studied the possible mechanisms of this specific regulation of virulent genes by HP1248. In addition, the expression level of HP1248 mRNA changed dramatically in response to a variety of altered environmental conditions, including pH and temperature. Hence, HP1248 in H. pylori seems to play a role in environmental sensing and in regulation of virulent phenotypes, such as motility and host apoptosis induction.Helicobacter pylori (27) is an important human pathogen, responsible for type B gastritis and peptic ulcers and for increasing the risk of gastric adenocarcinoma and mucosaassociated lymphoid tissue lymphoma of the stomach (6,32,35,42).Several bacterial factors, including flagella, various enzymes, and toxins, contribute to the full virulence of H. pylori (5,9,13,14,33). The motility of H. pylori is provided by flagella, the filaments of which consist of two flagellin types (38). The majority of the filament is composed of FlaA and FlaB (24). Motility in H. pylori is essential for colonization in gnotobiotic piglets (15). H. pylori infection can also induce apoptosis in gastric epithelial cells, lymphocytes, and macrophages (17,31,45) and could contribute to mucosal inflammation. In addition, the loss of activated macrophages is likely to decrease the effective immune response to the pathogen (17). Recently some apoptosis-inducing factors of H. pylori were examined (16, 25). However, the regulation mechanism of these virulence factors is not yet fully understood.In this study, we used an expression library of H. pylori (10) to clone a possible chlorhexidine resistance-related gene, HP1248. However, we suggested that the chlorhexidineresistant clone might be an overexpression artifact. On the other hand, HP1248 is similar to Escherichia coli vacB based on sequence similarity. Although its exact mechanism of action is unknown, vacB has been shown to encode RNase R and to be associated wi...

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Section: Resultsmentioning

confidence: 99%

“…We showed that several virulence-related genes were posttranscriptionally downregulated by HP1248, including HP0175, gtt, cagA, flaB, cheY, and HP1192. HP0175, cagA, and gtt can induce apoptosis of host cells (5,23,30,39). In addition, flaB is involved in the motility of H. pylori (37) and HP1192 is a putative motility protein.…”

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confidence: 99%

The 3′-to-5′ Exoribonuclease (Encoded by HP1248) ofHelicobacter pyloriRegulates Motility and Apoptosis-Inducing Genes

et al. 2009

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“…Here, we extend these findings and implicate two H. pylori virulence determinants, VacA and GGT, in DC tolerization. Both factors were previously known to share several important properties: They both facilitate murine colonization (16,17), inhibit human T-cell activation (18)(19)(20)25), and induce epithelial cell apoptosis (26,27). The evidence now provided here documents a unique role for VacA and GGT in DC tolerization and links the tolerizing effects of both factors on DCs to persistence: (i) The H. pylori-induced inhibition of DC maturation depends on the (nonredundant) activity of both factors; (ii) the induction of Treg properties in naive T cells by H. pylori-experienced DCs likewise depends on both factors, and strains lacking either VacA or GGT due to targeted gene deletion (iii) fail to colonize mice at wild-type levels, and, in the case of the ΔvacA mutant (iv) induce somewhat stronger Th1 and Th17 responses and gastric pathology and fail to protect against allergen-induced asthma.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance

Oertli

Noben

Engler

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

211

190

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Infection with the gastric bacterial pathogen Helicobacter pylori is typically contracted in early childhood and often persists for decades. The immunomodulatory properties of H. pylori that allow it to colonize humans persistently are believed to also account for H. pylori's protective effects against allergic and chronic inflammatory diseases. H. pylori infection efficiently reprograms dendritic cells (DCs) toward a tolerogenic phenotype and induces regulatory T cells (Tregs) with highly suppressive activity in models of allergen-induced asthma. We show here that two H. pylori virulence determinants, the γ-glutamyl transpeptidase GGT and the vacuolating cytotoxin VacA, contribute critically and nonredundantly to H. pylori's tolerizing effects on murine DCs in vitro and in vivo. The tolerancepromoting effects of both factors are independent of their described suppressive activity on T cells. Isogenic H. pylori mutants lacking either GGT or VacA are incapable of preventing LPS-induced DC maturation and fail to drive DC tolerization as assessed by induction of Treg properties in cocultured naive T cells. The Δggt and ΔvacA mutants colonize mice at significantly reduced levels, induce stronger T-helper 1 (Th1) and T-helper 17 (Th17) responses, and/or trigger more severe gastric pathology. Both factors promote the efficient induction of Tregs in vivo, and VacA is required to prevent allergen-induced asthma. The defects of the Δggt mutant in vitro and in vivo are phenocopied by pharmacological inhibition of the transpeptidase activity of GGT in all readouts. In conclusion, our results reveal the molecular players and mechanistic basis for H. pyloriinduced immunomodulation, promoting persistent infection and conferring protection against allergic asthma.bacterial virulence factors | hygiene hypothesis | persistent bacterial infection | human microbiota | persistence strategies T he bacterial pathogen Helicobacter pylori persistently colonizes the gastric mucosa of humans. It is typically acquired in early childhood (1) and, in the absence of antibiotic therapy, may persist for the entire lifespan of the host (2, 3). The extraordinary ability of H. pylori to resist a vigorous adaptive immune response driven in large part by T-helper 1 (Th1) and/or T-helper 17 (Th17)-polarized effector T cells (4, 5) has been attributed to its perfect adaptation to-and manipulation of-the human innate and adaptive immune systems (6). H. pylori has colonized its human host for at least 60,000 y (7) and during this long period of coevolution has evolved elaborate ways to systemically manipulate adaptive immune responses and to promote its persistence through the preferential induction of regulatory T-cell (Treg) over T-effector cell responses. Treg-predominant responses are characteristic of heavily colonized but asymptomatic carriers (4) and of children with particularly mild forms of Helicobacter-associated gastritis (8). Several recent functional studies using experimentally infected animals have implicated Tregs and dendritic cells (...

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“…H. felis and H. suis induce apoptosis in the murine gastric epithelial cell line GSM06 and in the human gastric adenocarcinoma cell line AGS (unpublished results). Gamma-glutamyltranspeptidase, which has been associated with the induction of apoptosis in gastric epithelial cells and the inhibition of T-cell proliferation by H. pylori (125,195,201), is also produced by gastric non-H. pylori Helicobacter species (Table 2).…”

Section: Virulence Factors Of Gastric Non-h Pylori Helicobacter Speciesmentioning

confidence: 99%

Gastric Helicobacters in Domestic Animals and Nonhuman Primates and Their Significance for Human Health

et al. 2009

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SUMMARY Helicobacters other than Helicobacter pylori have been associated with gastritis, gastric ulcers, and gastric mucosa-associated lymphoid tissue lymphoma in humans. These very fastidious microorganisms with a typical large spiral-shaped morphology were provisionally designated “H. heilmannii,” but in fact they comprise at least five different Helicobacter species, all of which are known to colonize the gastric mucosa of animals. H. suis, which has been isolated from the stomachs of pigs, is the most prevalent gastric non-H. pylori Helicobacter species in humans. Other gastric non-H. pylori helicobacters colonizing the human stomach are H. felis, H. salomonis, H. bizzozeronii, and the still-uncultivable “Candidatus Helicobacter heilmannii.” These microorganisms are often detected in the stomachs of dogs and cats. “Candidatus Helicobacter bovis” is highly prevalent in the abomasums of cattle but has only occasionally been detected in the stomachs of humans. There are clear indications that gastric non-H. pylori Helicobacter infections in humans originate from animals, and it is likely that transmission to humans occurs through direct contact. Little is known about the virulence factors of these microorganisms. The recent successes with in vitro isolation of non-H. pylori helicobacters from domestic animals open new perspectives for studying these microorganisms and their interactions with the host.

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γ-Glutamyltranspeptidase of Helicobacter pylori induces mitochondria-mediated apoptosis in AGS cells

Cited by 58 publications

References 32 publications

The 3′-to-5′ Exoribonuclease (Encoded by HP1248) ofHelicobacter pyloriRegulates Motility and Apoptosis-Inducing Genes

The 3′-to-5′ Exoribonuclease (Encoded by HP1248) ofHelicobacter pyloriRegulates Motility and Apoptosis-Inducing Genes

Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance

Gastric Helicobacters in Domestic Animals and Nonhuman Primates and Their Significance for Human Health

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