Virulence factor cytotoxin-associated gene A in Helicobacter pylori is downregulated by interferon-γin vitro

Zhao, Yinghui; Zhou, Yabin; Sun, Yuan; AiLian, Yu; Yu, Han; Li, Wenjuan; Liu, Zhifang; Zeng, Jiping; Li, Xi; Chen, Chunyan; Jia, Jihui

doi:10.1111/j.1574-695x.2010.00750.x

Cited by 8 publications

(9 citation statements)

References 34 publications

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“…Consistent with these findings, Sayi et al (48) further demonstrated the tumorigenic risk caused by IFN-g, although IFN-g also triggers clearance during H. pylori infection. For antimicrobial activity, in addition to activating macrophages for phagocytosis, CagA protein is inhibited by IFN-g through an asyet-unknown mechanism, as reported previously (28). To demonstrate the antimicrobial effect of IFN-g, we confirmed that pretreatment with IFN-g decreased CagA expression, as detected by Western blot analysis (Supplemental Fig.…”

Section: Discussionsupporting

confidence: 79%

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Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

Wang

Chen

Sheu

et al. 2014

The Journal of Immunology

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Helicobacter pylori infection not only induces gastric inflammation but also increases the risk of gastric tumorigenesis. IFN-γ has antimicrobial effects; however, H. pylori infection elevates IFN-γ–mediated gastric inflammation and may suppress IFN-γ signaling as a strategy to avoid immune destruction through an as-yet-unknown mechanism. This study was aimed at investigating the mechanism of H. pylori–induced IFN-γ resistance. Postinfection of viable H. pylori decreased IFN-γ–activated signal transducers and activators of transcription 1 and IFN regulatory factor 1 not only in human gastric epithelial MKN45 and AZ-521 but also in human monocytic U937 cells. H. pylori caused an increase in the C-terminal tyrosine phosphorylation of Src homology-2 domain–containing phosphatase (SHP) 2. Pharmacologically and genetically inhibiting SHP2 reversed H. pylori–induced IFN-γ resistance. In contrast to a clinically isolated H. pylori strain HP238, the cytotoxin-associated gene A (CagA) isogenic mutant strain HP238CagAm failed to induce IFN-γ resistance, indicating that CagA regulates this effect. Notably, HP238 and HP238CagAm differently caused SHP2 phosphorylation; however, imaging and biochemical analyses demonstrated CagA-mediated membrane-associated binding with phosphorylated SHP2. CagA-independent generation of reactive oxygen species (ROS) contributed to H. pylori–induced SHP2 phosphorylation; however, ROS/SHP2 mediated IFN-γ resistance in a CagA-regulated manner. This finding not only provides an alternative mechanism for how CagA and ROS coregulate SHP2 activation but may also explain their roles in H. pylori–induced IFN-γ resistance.

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Section: Discussionsupporting

confidence: 79%

“…Moreover, polymorphisms in IFNGRs affect H. pylori infection in human (27). IFN-g also confers antimicrobial activity directly against CagA expression in H. pylori infection (28) and prevents gastric carcinogenesis by inducing epithelial cell autophagy and T cell apoptosis (29). However, H. pylori may disrupt IFN-g signaling through an unknown mechanism (30).…”

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confidence: 99%

Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

Wang

Chen

Sheu

et al. 2014

The Journal of Immunology

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“…However, H. pylori can disrupt STAT1-mediated IFN- γ -induced signal transduction in epithelial cells [ 20 ]. Moreover, when H. pylori is exposed to IFN- γ ; the main virulence factor cytotoxin-associated gene A (CagA) is downregulated [ 21 ], which is beneficial for persistent colonization [ 22 ]. Thus, H. pylori may actively respond to altered IFN- γ levels for persistent colonization.…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pyloriOuter Membrane Protein 18 (Hp1125) Is Involved in Persistent Colonization by Evading Interferon-γSignaling

Shan

Han

et al. 2015

BioMed Research International

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Outer membrane proteins (OMPs) can induce an immune response. Omp18 (HP1125) of H. pylori is a powerful antigen that can induce significant interferon-γ (IFN-γ) levels. Previous studies have suggested that IFN-γ plays an important role in H. pylori clearance. However, H. pylori has multiple mechanisms to avoid host immune surveillance for persistent colonization. We generated an omp18 mutant (H. pylori 26695 and H. pylori SS1) strain to examine whether Omp18 interacts with IFN-γ and is involved in H. pylori colonization. qRT-PCR revealed that IFN-γ induced Omp18 expression. qRT-PCR and western blot analysis revealed reduced expressions of virulence factors CagA and NapA in H. pylori 26695 with IFN-γ treatment, but they were induced in the Δomp18 strain. In C57BL/6 mice infected with H. pylori SS1 and the Δomp18 strain, the Δomp18 strain conferred defective colonization and activated a stronger inflammatory response. Signal transducer phosphorylation and transcription 1 (STAT1) activator was downregulated by the wild-type strain but not the Δomp18 strain in IFN-γ-treated macrophages. Furthermore, Δomp18 strain survival rates were poor in macrophages compared to the wild-type strain. We concluded that H. pylori Omp18 has an important function influencing IFN-γ-mediated immune response to participate in persistent colonization.

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“…10 IFN-␥ plays a dual role in response to H. pylori infection; on the one hand, it induces gastric inflammation and promotes the appearance of pre-neoplastic lesions caused by the infection, and on the other, IFN-␥ reduces bacterial colonization and is essential for the elimination of the infection. [11][12] Previous studies found that IFN-␥ levels were higher in patients infected with H. pylori than in uninfected patients. 9,[13][14][15] In 2007, Wang et al found that in patients infected with cagA + H. pylori, the cellular immune response mediated by Th1 cells was associated with earlier stages of gastric carcinogenesis, whereas humoral immunity mediated by Th2 cells predominated in the advanced stages.…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori vacA and cagA genotype diversity and interferon gamma expression in patients with chronic gastritis and patients with gastric cancer

Martínez‐Carrillo¹,

Atrisco-Morales²,

Hernández-Pando³

et al. 2014

Revista de Gastroenterología de México (English Edition)

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Background: Helicobacter pylori (H. pylori) is the main risk factor for the development of chronic gastritis, gastric ulcer, and gastric cancer. In H. pylori-infected individuals, the clinical result is dependent on various factors, among which are bacterial components, the immune response, and environmental influence. Aims: To compare IFN-␥ expression with the H. pylori vacA and cagA genotypes in patients with chronic gastritis and patients with gastric cancer. Methods: Ninety-five patients diagnosed with chronic gastritis and 20 with gastric cancer were included in the study. Three gastric biopsies were taken; one was used for the molecular detection and genotyping of H. pylori; another was fixed in absolute alcohol and histologic sections were made for determining IFN-␥ expression through immunohistochemistry.ଝ Please cite this article as: Martínez-Carrillo DN, Atrisco-Morales J, Hernández-Pando R, Reyes-Navarrete S, Betancourt-Linares R, Cruzdel Carmen I, et al. Diversidad de los genotipos vacA y cagA de Helicobacter pylori y expresión de interferón gamma en pacientes con gastritis crónica y cáncer gástrico. Revista de Gastroenterología de México. 2014;79:220---228.Diversidad de los genotipos vacA y cagA de Helicobacter pylori y expresión de interferón gamma en pacientes con gastritis crónica y cáncer gástrico ResumenAntecedentes: El H. pylori es el principal factor de riesgo para el desarrollo de gastritis crónica, úlcera gástrica y cáncer gástrico. El resultado clínico en infectados por esta bacteria depende de varios factores, entre ellos los componentes bacterianos, la respuesta inmune, y la influencia del medio ambiente. Objetivo: Comparar la expresión de IFN-␥ con los genotipos vacA y cagA de H. pylori en pacientes con gastritis crónica y cáncer gástrico. Pacientes y métodos: Se incluyeron 95 pacientes con diagnóstico de gastritis crónica y 20 con cáncer gástrico. Se tomaron 3 biopsias gástricas, una se utilizó para la identificación molecular y genotipificación de H. pylori. Otra fue fijada en alcohol absoluto y realizaron cortes histológicos para determinar la expresión de IFN-␥ por inmunohistoquímica. Resultados: No se encontraron diferencias en las células que expresaron IFN-␥ entre pacientes con gastritis crónica (mediana del porcentaje de células positivas: 82.6% en pacientes sin H. pylori y 82% en personas infectadas) y cáncer gástrico (70.5% en pacientes H. pylorinegativos y 78.5% en infectados). En pacientes con gastritis crónica infectados por H. pylori vacAs2m2/cagA − la expresión de IFN-␥ fue del 69%, en pacientes con H. pylori vacAs1m2/cagA − fue de 86.5%, en vacAs1m1/cagA − del 86.5%, y en vacAs1m1/cagA + del 82%. En cáncer se encontraron datos similares. Conclusión: La expresión de INF-␥ varía dependiendo del genotipo vacA y cagA de H. pylori, pero no de acuerdo a la presencia de gastritis crónica o cáncer gástrico.

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Virulence factor cytotoxin-associated gene A in Helicobacter pylori is downregulated by interferon-γin vitro

Cited by 8 publications

References 34 publications

Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

Helicobacter pyloriOuter Membrane Protein 18 (Hp1125) Is Involved in Persistent Colonization by Evading Interferon-γSignaling

Helicobacter pylori vacA and cagA genotype diversity and interferon gamma expression in patients with chronic gastritis and patients with gastric cancer

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