Response of Gastric Epithelial Progenitors to Helicobacter pylori Isolates Obtained from Swedish Patients with Chronic Atrophic Gastritis
Response of Gastric Epithelial Progenitors to Helicobacter pylori Isolates Obtained from Swedish Patients with Chronic Atrophic Gastritis
复制标题
胃上皮祖细胞对从瑞典慢性萎缩性胃炎患者体内获得的幽门螺杆菌分离物的反应
DOI：
10.1074/jbc.m109.052738
复制
发表时间：
2009-10-30
影响因子：
4.8
通讯作者：
Gordon, Jeffrey I.
中科院分区：
文献类型：
--
作者：
Giannakis, Marios;Backhed, Helene Kling;Gordon, Jeffrey I.
幽门螺杆菌感染与某些人的胃腺癌有关，尤其是那些患有慢性萎缩性胃炎 (ChAG) 的人。具有 ChAG 样表型的转基因无菌小鼠的胃上皮祖细胞 (GEP) 含有幽门螺杆菌的细胞内集合。为了表征幽门螺杆菌对 ChAG 的适应性，我们对从 6 个个体获得的 24 个分离株的基因组进行了测序，每个分离株在 4 年的时间间隔内进行采样，因为它们是否从正常胃组织学进展为 ChAG 和/或腺癌。研究参与者体内的幽门螺杆菌种群大部分是克隆性的，并且无论疾病状态如何，都非常稳定。 GeneChip 对培养的小鼠胃干细胞样系 (mGEP) 对测序菌株感染的反应进行了研究，产生了 695 个转录本数据集，这些转录本数据集 (i) 在 ChAG 相关分离株感染后差异表达，但在“正常”或热灭活的 ChAG 分离株中没有差异表达，(ii) 富含与一般肿瘤发生和特定情况下胃癌发生相关的基因和基因功能。 mGEP 感染期间 ChAG 菌株的转录谱揭示了一系列反应，包括 hopZ（属于外膜蛋白家族的粘附素）的上调。野生型和 Delta hopZ 菌株的表达谱揭示了许多由 HopZ 调节的 pH 调节基因，包括 hopP，它与体内 GEP 产生的唾液酸化聚糖结合。 hopZ 的基因失活导致了限生转基因小鼠的胃部出现健康缺陷，但野生型同窝小鼠的胃部却没有出现这种缺陷。这项研究阐明了一种方法，用于识别 ChAG 相关幽门螺杆菌菌株特有的 GEP 反应以及对 ChAG 胃生态系统模型中的生存至关重要的细菌基因。
Helicobacter pylori infection is associated with gastric adenocarcinoma in some humans, especially those that develop an antecedent condition, chronic atrophic gastritis (ChAG). Gastric epithelial progenitors (GEPs) in transgenic gnotobiotic mice with a ChAG-like phenotype harbor intracellular collections of H. pylori. To characterize H. pylori adaptations to ChAG, we sequenced the genomes of 24 isolates obtained from 6 individuals, each sampled over a 4-year interval, as they did or did not progress from normal gastric histology to ChAG and/or adenocarcinoma. H. pylori populations within study participants were largely clonal and remarkably stable regardless of disease state. GeneChip studies of the responses of a cultured mouse gastric stem cell-like line (mGEPs) to infection with sequenced strains yielded a 695-member dataset of transcripts that are (i) differentially expressed after infection with ChAG-associated isolates, but not with a "normal" or a heat-killed ChAG isolate, and (ii) enriched in genes and gene functions associated with tumorigenesis in general and gastric carcinogenesis in specific cases. Transcriptional profiling of a ChAG strain during mGEP infection disclosed a set of responses, including up-regulation of hopZ, an adhesin belonging to a family of outer membrane proteins. Expression profiles of wild-type and Delta hopZ strains revealed a number of pH-regulated genes modulated by HopZ, including hopP, which binds sialylated glycans produced by GEPs in vivo. Genetic inactivation of hopZ produced a fitness defect in the stomachs of gnotobiotic transgenic mice but not in wild-type littermates. This study illustrates an approach for identifying GEP responses specific to ChAG-associated H. Pylori strains and bacterial genes important for survival in a model of the ChAG gastric ecosystem.