GENETIC REQUIREMENTS OF HELICOBACTER PYLORI INFECTION

项目摘要/摘要 幽门螺杆菌慢性感染着全球50%人口的胃部。十到 30%的感染者会出现严重的疾病，包括消化性溃疡和胃癌15。 幽门螺杆菌相关疾病不能完全归因于特定细菌毒素的表达。 相反，我们的总体工作假设是幽门螺杆菌疾病是这种相互作用的副产品 在建立和维持感染所需的细菌因素和 由此产生的宿主防御。这种相互作用是动态的，细菌和宿主都在转换 几十年的感染。为了研究这一复杂的过程，我们利用小鼠感染模型并研究 人类临床分离株的遗传变异。我们的幽门螺杆菌活体筛查 上一次资助期间的定植基因显示，29%的测试基因有定植 缺陷和我们60%的定植基因显示了菌株特有的表型16。这一分析，超过了 基因组的一半，证实了先前涉及的途径，但也识别了意想不到的和 研究较少的基因类别，包括参与DNA摄取和修饰的基因以及一个 大量的假想蛋白质(81)。在我们的更新中，我们专注于完成我们的全球分析 并探索基因参与胃定植的机制 在天然能力的DNA转化和重组的基础上促进DNA修复 感染。幽门螺杆菌的天然能力允许超级感染菌株之间的重组 在菌株内产生的新等位基因的感染和传播过程中产生新的基因类型 人口。我们将探索DNA交换和基于重组的修复在 单一菌株的感染，包括1。)修复在感染期间遇到的DNA损伤2。) 适应性遗传变异的产生和3)。影响基因转换事件的催化作用 促进(或限制)定居的基因的表达。我们为完全绘制基因图谱所做的努力 对毒力的贡献将确定持续感染的媒介和基因研究 临床人群的变化将显示这些介质在慢性炎症期间如何适应 这与感染有关，并导致严重疾病(溃疡、癌症)。我们对人类社会的研究 幽门螺杆菌促进遗传交流和多样化的机制也应增加 了解抗菌素耐药性的传播，这是一个日益严重的临床问题 幽门螺杆菌的治疗。这符合NIAID了解和治疗传染病的使命。

PROJECT SUMMARY / ABSTRACT Helicobacter pylori chronically infect the human stomach of 50% of the population worldwide. Ten to 30% of those infected will present with severe disease including peptic ulcers and gastric cancers15. H. pylori associated diseases cannot be attributed solely to expression of particular bacterial toxins. Instead, our overall working hypothesis is that H. pylori disease is a by-product of the interaction between bacterial factors necessary for establishing and maintaining infection and the resultant host defenses. This interaction is dynamic with both the bacteria and host changing over decades of infection. To study this complex process, we utilize a mouse model of infection and study genetic variation among isolates from human clinical populations. Our in vivo screen for H. pylori colonization genes in the previous funding period showed 29% of genes tested had a colonization defect and 60% of our colonization genes showed strain specific phenotypes16. This analysis, of over half of the genome, confirmed pathways previously implicated, but also identified unexpected and less well studied classes of genes, including genes involved in DNA uptake and modification plus a large number of hypothetical proteins (81). In our renewal we focus on completing our global analysis of genes contributing to stomach colonization and explore the mechanisms by which genes involved in natural competence for DNA transformation and recombination-based DNA repair promote infection. H. pylori's natural competence allows recombination between super-infecting strains to generate new genotypes during infection and spread of new alleles generated within a strain population. We will explore the roles DNA exchange and recombination-based repair may play during infection of a single strain including 1.) repair of DNA damage encountered during infection 2.) generation of adaptive genetic variation and 3). catalysis of genetic switching events affecting the expression of genes promoting (or limiting) colonization. Our efforts to fully map the genes contributing to virulence will identify the mediators of persistent infection and studies of genetic variation in the clinical population will show how these mediators adapt during chronic inflammation that is associated with infection and leads to severe disease (ulcer, cancer). Our study of the mechanisms by which H. pylori promotes genetic exchange and diversification should also increase understanding of the spread of antimicrobial resistance, an increasing clinical problem in the treatment of H. pylori. This fits the mission of NIAID to understand and treat infectious diseases.