Genetic requirements of Helicobacter pylori infection

项目总结 幽门螺杆菌慢性感染世界上一半的人的胃，大约三分之一的人 美国人口。幽门螺杆菌在所有宿主中都会引起炎症，10%-20%的感染者会出现 严重疾病，包括消化性溃疡和胃腺癌。所有与幽门螺杆菌相关的疾病 依赖于这种有机体建立持续感染和诱导慢性炎症的能力。 胃的慢性炎症可导致额外的组织变化，包括萎缩性胃炎(丢失 产酸壁细胞)、痉挛多肽表达化生(SPEM)、肠 会增加腺癌风险的化生(IM)和异型增生。在之前的资助期，我们 幽门螺杆菌菌株在慢性人类感染期间对这些组织变化的记录遗传适应 利用全基因组序列分析、广泛的表型和分子变异相结合的方法 跟踪临床和基于人群的样本。我们还发现，幽门螺杆菌能主动调节 促炎症细胞膜侧支递送相关的免疫微环境 通过CAG类型IV分泌系统(T4SS)分泌毒素CagA期间的代谢物。这些数据 结合临床数据显示早期癌切除后异时性癌的发生率较高 持续感染幽门螺杆菌的个体促使我们重新思考幽门螺杆菌致癌的模型，而不仅仅是它 作为炎症发起者的角色。我们认为幽门螺杆菌通过 持续重塑组织环境，为长期坚持创造有利的利基环境 和变速箱。因此，幽门螺杆菌病是细菌因素相互作用的副产品。 对于建立和维持传播的感染和由此产生的宿主防御是必要的。在我们的 更新我们建议利用这些培养集合和新开发的小鼠模型来阐明 驱动这些适应的遗传机制以及随之而来的表型变化 化生进展。我们的具体目标是：1)识别慢性阻塞性肺疾病患者的适应性遗传变异 感染和癌前组织变化，2)检查慢性感染期间的表型变化和 适应不同的小生境和3)评估上皮间和髓系间的相互作用 在CAG中，T4SS依赖于先天免疫激活、细菌控制和组织重塑。 我们对导致慢性定植的基因和机制的研究将确定H。 幽门螺杆菌持续感染。我们对胃部感染过程中的遗传变异的研究将显示这些 在导致严重疾病(癌症)的慢性炎症期间，介质会适应。

PROJECT SUMMARY Helicobacter pylori chronically infects the human stomach of half the world and approximately a third of the US population. H. pylori induces inflammation in all hosts and 10-20% of those infected will present with severe disease including peptic ulcers and gastric adenocarcinoma. All H. pylori associated diseases depend on the ability of this organism to establish a persistent infection and induce chronic inflammation. Chronic inflammation in the stomach can lead to additional tissue changes including atrophic gastritis (loss of acid-producing parietal cells), spasmolytic polypeptide-expressing metaplasia (SPEM), intestinal metaplasia (IM) and dysplasia that increase risk for adenocarcinoma. In the prior funding period, we documented genetic adaptation of H. pylori strains to these tissue changes during chronic human infection using a combination of whole genome sequence analysis, extensive phenotyping and molecular variant tracking in clinical and population-based samples. We also showed that H. pylori actively modulates the immune microenvironment through collateral delivery of proinflammatory cell envelope associated metabolites during secretion of the toxin CagA via the Cag Type IV Secretion System (T4SS). These data combined with clinical data revealing higher rates of metachronous cancer after early cancer resection in individuals with sustained Hp infection lead us to rethink the model of H. pylori carcinogenesis beyond its role as an initiator of inflammation. We propose that H. pylori promotes carcinogenesis through continual remodeling of the tissue environment to create a favorable niche for long term persistence and transmission. Thus, H. pylori disease is a by-product of the interaction between bacterial factors necessary for establishing and maintaining infection for transmission and resultant host defenses. In our renewal we propose to leverage these culture collections and newly developed mouse models to elucidate the genetic mechanisms that drive these adaptations and the resultant phenotypic changes that accompany metaplastic progression. Our specific aims are to 1) Identify adaptive genetic variation during chronic infection and preneoplastic tissue changes, 2) Examine phenotypic changes during chronic infection and adaptation to distinct niches and 3) Evaluate the interplay between the epithelial and myeloid compartment in Cag T4SS dependent innate immune activation, bacterial control, and tissue remodeling. Our study of the genes and mechanisms contributing to chronic colonization will identify the mediators of H. pylori persistent infection. Our studies of genetic variation during stomach infection will show how these mediators adapt during the chronic inflammation that leads to severe disease (cancer).