Genetic requirements of Helicobacter pylori infection

项目摘要 幽门螺杆菌慢性感染世界上一半的人的胃，大约三分之一的人的胃。 美国人口。H.幽门螺杆菌在所有宿主中诱导炎症，10-20%的感染者将出现 严重疾病包括消化性溃疡和胃腺癌。全是H。幽门相关疾病 依赖于这种生物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其他组织变化，包括萎缩性胃炎（损失 产酸壁细胞），痉挛性多肽表达化生（SPEM），肠 化生（IM）和异型增生，增加腺癌的风险。在上一个融资周期，我们 证明了H.幽门螺杆菌菌株在慢性人类感染期间对这些组织变化的影响 使用全基因组序列分析、广泛的表型分析和分子变异的组合， 在临床和基于人群的样本中进行跟踪。我们还证明了H.幽门螺杆菌主动调节 免疫微环境通过促炎细胞包膜相关侧支传递 在毒素CagA通过CagIV型分泌系统（T4 SS）分泌期间，CagA代谢产物。这些数据 结合临床数据显示早期癌症切除术后异时性癌症的发生率较高， 持续感染Hp的个体使我们重新思考H.幽门螺杆菌致癌作用超出其 作为炎症的引发剂。我们建议H.幽门螺杆菌通过促进 持续重塑组织环境，为长期持久性创造有利的生态位 和传输。因此，H.幽门螺杆菌疾病是细菌因素之间相互作用的副产品 这是建立和维持感染传播和由此产生的宿主防御所必需的。在我们 更新，我们建议利用这些文化收藏和新开发的小鼠模型，以阐明 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）在慢性疾病中识别适应性遗传变异 感染和癌前组织变化，2）检查慢性感染期间的表型变化， 对不同小生境的适应和3）评价上皮和骨髓间室之间的相互作用 在Cag T4 SS依赖性先天免疫激活、细菌控制和组织重塑中。 我们对慢性定植的基因和机制的研究将确定H. 幽门持续感染。我们对胃感染期间遗传变异的研究将显示这些基因是如何被激活的。 介质在导致严重疾病（癌症）的慢性炎症期间适应。

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).