Helicobacter pylori–Induced Rev-erbα Fosters Gastric Bacteria Colonization by Impairing Host Innate and Adaptive Defense
Fangyuan MaoYi-pin LvChuan-jie HaoYong‐sheng TengYugang LiuPing ChengShiming YangWeisan ChenTao LiuQuanming ZouRui XieJingyu XuYuan Zhuang
11
Citation
37
Reference
10
Related Paper
Citation Trend
Abstract:
Background & AimsRev-erbα represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erbα in Helicobacter pylori infection are presently unknown.MethodsRev-erbα was examined in gastric samples from H pylori-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with H pylori for Rev-erbα regulation assays. Gastric tissues from Rev-erbα–/– and wild-type (littermate control) mice or these mice adoptively transferred with CD4+ T cells from IFN-γ–/– and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for bacteria colonization. GECs, CD45+CD11c–Ly6G–CD11b+CD68– myeloid cells and CD4+ T cells were isolated, stimulated and/or cultured for Rev-erbα function assays.ResultsRev-erbα was increased in gastric mucosa of H pylori-infected patients and mice. H pylori induced GECs to express Rev-erbα via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-κB directly binding to Rev-erbα promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and β-defensin-1 expression, which resulted in impaired bactericidal effects against H pylori of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine CCL21 expression, which led to decreased gastric influx of CD45+CD11c–Ly6G–CD11b+CD68– myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of H pylori-specific Th1 cell response.ConclusionsOverall, this study identifies a model involving Rev-erbα, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H pylori. Rev-erbα represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erbα in Helicobacter pylori infection are presently unknown. Rev-erbα was examined in gastric samples from H pylori-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with H pylori for Rev-erbα regulation assays. Gastric tissues from Rev-erbα–/– and wild-type (littermate control) mice or these mice adoptively transferred with CD4+ T cells from IFN-γ–/– and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for bacteria colonization. GECs, CD45+CD11c–Ly6G–CD11b+CD68– myeloid cells and CD4+ T cells were isolated, stimulated and/or cultured for Rev-erbα function assays. Rev-erbα was increased in gastric mucosa of H pylori-infected patients and mice. H pylori induced GECs to express Rev-erbα via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-κB directly binding to Rev-erbα promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and β-defensin-1 expression, which resulted in impaired bactericidal effects against H pylori of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine CCL21 expression, which led to decreased gastric influx of CD45+CD11c–Ly6G–CD11b+CD68– myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of H pylori-specific Th1 cell response. Overall, this study identifies a model involving Rev-erbα, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H pylori.Keywords:
CD11c
CagA
To investigate the correlation among vacA genotypes, cagA gene, VacA, serum CagA antibodies of Helicobacter pylori (H. pylori) and gastroduodenal diseases.vacA genotypes and cagA gene of 62 H. pylori strains isolated from patients with chronic gastritis, peptic ulcer and gastric cancer were tested by polymerase chain reaction, and Hela cell assay for VacA activity in vitro. Serum CagA antibodies were measured by EIA method in the same patients.All 62 H. pylori strains possessed the vacA gene and vacA genotypes of all strains were type s1a/m2. Total positive rate of cagA gene was 56.45%; the positive rates of cagA gene of H. pylori strains isolated from patients with chronic gastritis, peptic ulcer and gastric cancer were 55.56%, 54.17% and 63.64%, respectively (P > 0.05). The total positive rate of VacA was 37.10%; the positive rates of VacA produced by H. pylori strains isolated from patients with chronic gastritis, peptic ulcer and gastric cancer were 33.33%, 29.17% and 63.64%, respectively (P > 0.05). The positive rates of CagA antibodies in patients with chronic gastritis, peptic ulcer and gastric cancer were 70.37%, 79.17% and 40.00%, respectively (P > 0.05). The total positive rate of CagA antibodies was 68.85%.There was no correlation among cagA gene and vacA genotypes of H. pylori, VacA, serum CagA antibodies and various gastroduodenal diseases.
CagA
Chronic gastritis
Atrophic gastritis
Cite
Citations (16)
Previous studies have implicated CagA [encoded by cytotoxin-associated gene A (cagA)] in Helicobacter pylori-associated gastroduodenal pathology and distinct subgenotypes of cagA may circulate in different pathological manifestations of cagA-positive H. pylori infection. To investigate cagA genotype and variants in Chinese H. pylori strains and explore their relationship with gastroduodenal diseases, the cagA status of 82 Chinese H. pylori strains was examined and variation in size of the 3' region of cagA in 71 of these strains was analysed by PCR. cagA was detected in 28 (100%) of 28 strains from peptic ulcer patients, two (100%) of two strains from gastric cancer patients, 32 (94.1%) of 34 strains from chronic gastritis patients and 17 (94.4%) of 18 strains from healthy volunteers. PCR products of the cagA 3' variable region were obtained from 71 (92.2%) of 77 Chinese H. pylori strains and could be classified into subgenotypes I, II and III, which gave PCR products of around 825, 900 and 950 bp, respectively. Subgenotype I cagA predominated in Chinese H. pylori strains (67/71), whereas subgenotype II cagA presented in two isolates from patients with chronic gastritis and subgenotype III presented in two isolates from healthy volunteers. Therefore, neither cagA nor its 3' region variants can be used as a sole marker for the presence of particular H. pylori-related gastroduodenal diseases in the Chinese population.
CagA
Chronic gastritis
Cite
Citations (46)
Abstract Background Helicobacter pylori has been strongly associated with chronic gastritis, peptic and duodenal ulcers, and it is a risk factor for gastric cancer. Three major virulence factors of H. pylori have been described: the vacuolating toxin (VacA), the cytotoxin-associated gene product (CagA) and the adhesion protein BabA2. Since considerable geographic diversity in the prevalence of H. pylori virulence factors has been reported, the aim of this work was to establish the H. pylori and vacA , cagA and babA2 gene status in 238 adult patients, from a marginal urban area of Mexico, with chronic gastritis. Methods H. pylori was identified in cultures of gastric biopsies by nested PCR. vacA and cagA genes were detected by multiplex PCR, whereas babA2 gene was identified by conventional PCR. Results H. pylori -positive biopsies were 143 (60.1%). All H. pylori strains were vacA + ; 39.2% were cagA + ; 13.3% were cagA + babA2 + and 8.4% were babA2 + . Mexican strains examined possessed the vacA s1, m1 (43.4%), s1, m2 (24.5%), s2, m1 (20.3%) and s2, m2 (11.9%) genotypes. Conclusion These results show that the Mexican patients suffering chronic gastritis we have studied had a high incidence of infection by H. pylori . Forty four percent (63/143) of the H. pylori strains analyzed in this work may be considered as highly virulent since they possessed two or three of the virulence markers analyzed: vacA s1 cagA babA2 (9.8%, 14/143), vacA s1 babA2 (4.9%, 7/143), and vacA s1 cagA (29.4%, 42/143). However, a statistically significant correlation was not observed between vacAs1 , cagA and babA2 virulence markers (χ 2 test; P > 0.05).
CagA
Virulence factor
Chronic gastritis
Pathogenicity island
Cite
Citations (58)
ABSTRACT The babA2 and cagA genes were investigated in 208 Brazilian Helicobacter pylori strains. A strong association between babA2 and duodenal ulcer or gastric carcinoma was observed, even after adjusting for confounding factors, such as age, gender, and cagA status. cagA -positive strains were also independently associated with H . pylori -related diseases.
CagA
Spirillaceae
Gastric carcinoma
Cite
Citations (80)
ABSTRACT There is continuing interest in identifying Helicobacter pylori virulence factors that might predict the risk for symptomatic clinical outcomes. It has been proposed that iceA and cagA genes are such markers and can identify patients with peptic ulcers. We compared H. pylori isolates from four countries, looking at the cagA and vacA genotypes, iceA alleles, and presentation of the infection. We used PCR to examine iceA , vacA , and cagA status of 424 H. pylori isolates obtained from patients with different clinical presentations (peptic ulcer, gastric cancer, and atrophic gastritis). The H. pylori isolates examined included 107 strains from Bogota, Colombia, 70 from Houston, Tex., 135 from Seoul, Korea, and 112 from Kyoto, Japan. The predominant genotype differed among countries: the cagA -positive iceA1 vacA s1c-m1 genotype was predominant in Japan and Korea, the cagA -positive iceA2 vacA s1b-m1 genotype was predominant in the United States, and the cagA -positive iceA2 vacA s1a-m1 genotype was predominant in Colombia. There was no association between the iceA , vacA , or cagA status and clinical outcome in patients in the countries studied. iceA status shows considerable geographic differences, and neither iceA nor combinations of iceA , vacA , and cagA were helpful in predicting the clinical presentation of an H. pylori infection.
CagA
Cite
Citations (491)
Background : Determination of vacA mosaicism may be important because specific Helicobacter pylori vacA genotype can be used to predict different clinical outcome. The aim of this study was to assess the relationship of vacA genotypes of Helicobacter pylori to cagA status and its development of peptic ulcer diseases in Korean patients. Methods : Gastric biopsy specimens were obtained from 53 patients with gastric ulcer (GU), 57 with duodenal ulcer (DU) and 26 with chronic gastritis (CG) patients; all patients were infected with Helicobacter pylori. Bacterial mRNAs in the gastric mucosa were amplified by RT-PCR, using synthetic oligonucleotide primers specific for the vacA and the cagA gene. Patients with vacA s1 subtype were further examined to determine whether they had s1a or s1b subtype. Results : There was no correlation in frequency of vacA s1 and/or s1a genotype between CG and either GU or DU, as the vacA s1 and s1a/m1 were present in the majority of strains independent of clinical status (s1 ; 100.0% versus 94.3 % or 93.0 % and s1a/m1 : 76.9% versus 62.3% or 64.9%, respectively). Likewise, there was no difference in the prevalence of the cagA gene between CG and either GU or DU patients (92.3% versus 90.6% or 98.2%, respectively). In addition, the cagA-negative status did not predict the presence of vacA s2 genotype. Conclusion : These results strongly suggest that either cagA or vacA s1 and/or s1a is not proved to be a useful marker to distinguish disease-specific Helicobacter pylori strains for the development of peptic ulcer diseases in Korean patients.
CagA
Chronic gastritis
Helicobacter
Spirillaceae
Cite
Citations (16)
Background: Helicobacter pylori is an agent of gastric cancer that was classified as a group I carcinogen. cagA and vacA genes of H. pylori play important roles in the pathogenesis of gastroduodenal diseases. This research aimed to: (1) To determine the prevalence of cagA and vacA genotypes of H. pylori among patients with gastroduodenal diseases. (2) To investigate the association between cagA and vacA genotypes and gastroduodenal diseases. Patients and methods: One hundred and fifteen gastroduodenal disease patients infected with H. pylori were enrolled in this study. cagA and vacA genotypes were determined by PCR. Result: The rate of cagA-positive H. pylori strains was 80%. The most common genotype combinations were cagA (+)/ vacA s1m1i1 (39.1%) and cagA (+)/vacA s1m2i1 (25.2%). The cagA (+)/vacA s1m1i1 strain was predominant in peptic ulcer group (59.3%), whereas the cagA (+)/vacA s1m2i1 strain accounted for a high rate in gastric cancer group (75%). Conclusion: Prevalence of H. pylori strains carrying the cagA gene was quite high, and vacA smi genotypes were diverse. cagA (+)/vacA s1m1i1 strain was associated with peptic ulcer disease while cagA (+)/vacA s1m2i1 strain was associated with gastric cancer. Key words: Helicobacter pylori, gene cagA, gene vacA, gastroduodenal diseases.
CagA
Cite
Citations (0)
Резюме. Цель — оценка влияния токсигенных (cagA+, vacA+) штаммов Helicobacter pylori (H. pylori) на качество жизни пациентов с язвой желудка и двенадцатиперстной кишки в сочетании с артериальной гипертензией и сахарным диабетом 2-го типа. Методы исследования: верификацию диагноза проводили методом фиброгастродуоденоскопии с помощью аппарата «GIF-Q40» с прицельной биопсией с использованием тест-системы «ХЕЛИК®» с индикаторными трубками. Гены cagA и vacA H. pylori в биоптатах определяли с помощью наборов реагентов «Хеликопол». Контроль эффективности эрадикации проводили через 4 нед после завершения лечения ингибиторами протонной помпы и антибактериальными средствами с помощью уреазного дыхательного теста и иммунохроматографических тест-систем для выявления антигена H. pylori в фекалиях «CITO TEST® H. Рylori Ag». Результаты. Установлено, что жизнеспособность, психическое здоровье и физическая ролевая активность наиболее повышены в группах больных пептической язвой желудка и двенадцатиперстной кишки в сочетании с артериальной гипертензией и сахарным диабетом. Вывод. Применение комбинированной терапии улучшило состояние пациентов. Добавление к антихеликобактерной терапии пробиотика способствовало повышению качества их жизни.
CagA
Spirillaceae
Helicobacter Infections
Cite
Citations (2)
ABSTRACT The cagA gene was detected in 100% of 16 Helicobacter pylori isolates from patients with gastric carcinoma versus 78% of 18 isolates from patients with duodenal ulcers ( P = 0.344) and only 64% of 22 isolates from patients with gastritis only ( P = 0.005) in Brazil. Also, there was a significant association between isolation of cagA + s1-type vacA H. pylori in cases of stomach cancer and ulcers as opposed to cases of gastritis only ( P = 0.004), but this was not true in Houston ( P = 0.238), where 94% of all isolates were cagA + .
CagA
Spirillaceae
Cite
Citations (75)
Актуальность. Инфекция Helicobacter pylori является важным фактором хронического гастрита (ХГ) и дуоденальной язвы у детей. За последнее десятилетие установлена разная вирулентность штаммов H.pylori, которая зависит от его генов токсигенности. Цель: изучить клинические проявления, эндоскопические и гистологические изменения слизистой оболочки желудка (СОЖ) у детей с хроническим гастритом, индуцированным H.pylori, с разной его токсигенностью. Материалы и методы. Проведено клинико-инструментальное обследование 136 детей с хроническим гастритом, индуцированным H.pylori, в возрасте 7–17 лет (основная группа) и 30 здоровых детей этого же возраста (контрольная группа). Пациенты были разделены на 2 группы: IА группу составили 72 ребенка с хроническим гастритом, индуцированным H.pylori CagA «+»; IБ группу — 64 ребенка с хроническим гастритом, индуцированным H.pylori CagA «–», по результатам определения суммарных антител IgG к антигену CagA сыворотки крови и/или определения антигена CagA в биоптатах СОЖ методом полимеразной цепной реакции. Изучали и анализировали клинические проявления, эндоскопические и гистологические изменения слизистой оболочки желудка. Статистическая обработка проводилась с помощью пакета статистических программ Statgrafics 16.0. Результаты. У детей с ХГ, индуцированным H.pylori CagA «+» (IА группа), клинические проявления болевого абдоминального и диспептического синдромов существенно не отличаются от таковых у детей с ХГ, индуцированным H.pylori CagA «–» (ІБ группа). Не выявлены существенные эндоскопические изменения в виде эритематозной гастропатии и антральной нодулярности как у детей с ХГ, индуцированным H.pylori CagA «+», так и у детей с ХГ, индуцированным H.pylori CagA «–». Гистологические изменения в ІА и ІБ группах были разные: детям с ХГ, индуцированным H.pylori CagA «+», свойственны II и I степень активности воспаления и ІІ, І, ІІІ степени обсемененности Н.pylori слизистой оболочки желудка, а детям с ХГ, индуцированным H.pylori CagA «–», свойственны I, II степень активности воспаления слизистой оболочки желудка и II и I степень обсемененности Н.pylori. Выводы. Клиническими проявлениями ХГ, индуцированного H.pylori, у детей в стадии обострения является эпигастральная боль, симптомы диспепсии и хронического интоксикационного синдрома. Эндоскопическими проявлениями являются эритематозная гастропатия и/или антральная нодулярнисть. У детей с ХГ, индуцированным H.pylori СagA «+», и у детей с ХГ, индуцированным H.pylori СagA «–», по клиническим и эндоскопическим проявлениям существенного различия не выявлено. Гистологическим изменением СОШ при ХГ, индуцированном H.pylori, в стадии обострения является диффузная лимфоцитарно-плазмоцитарная инфильтрация собственной пластинки СОЖ с нарушением эпителия. При ХГ, индуцированным H.pylori СagA «+», преобладает II и III степень обсеменения H.pylori в сочетании с I и II степенью активности воспаления СОЖ. При ХГ, индуцированном H.pylori СagA «–», преобладает II и I степень обсеменения H.pylori СОЖ. У детей с ХГ, индуцированным H.pylori, целесообразно диагностировать его токсигенность CagA «+» для оценки H.pylori CagA-статуса ребенка.
CagA
Spirillaceae
Cite
Citations (0)