Genetic Requirements of Helicobacter pylori Infection

描述(由申请者提供)：幽门螺杆菌慢性感染世界上一半的人的胃和大约三分之一的美国人口。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的疾病，包括消化性溃疡和胃癌。所有与幽门螺杆菌相关的疾病都依赖于这种微生物建立持续感染和引发慢性炎症的能力。因此，幽门螺杆菌病是建立和维持感染所必需的细菌因素与由此产生的宿主防御之间相互作用的副产品。这种相互作用是动态的，细菌和宿主在数十年的感染过程中都会发生变化。为了研究这一复杂的过程，我们利用了小鼠感染模型，并研究了来自人类临床人群的分离株之间的遗传变异。在以前的资助时期的工作建立了必要的工具和方法，以采取功能基因组方法来确定这种生物的致病分子机制，它在进化上与更好地研究肠道病原体相去甚远，包括全基因组测序、体内定植筛选以及随机和有序序列定义的突变体库。我们的遗传研究和基于群体的研究的融合推动了我们拟议的DNA修复、摄取和遗传多样性以及似乎影响宿主反应的细胞膜蛋白的研究重点。这将通过三个目标完成：1.评估DNA修复作为根除幽门螺杆菌治疗的目标；2.探索在人类和小鼠胃定植模型中传播和慢性感染过程中基因变异的机制和后果；3.对促进和抑制感染的细菌因子进行功能分析。我们对毒力相关基因的研究将确定持续感染的媒介，对TE临床人群的遗传变异的研究将显示这些媒介在与感染相关的慢性炎症期间如何适应，并导致严重疾病(溃疡、癌症)。我们对幽门螺杆菌促进基因交流和多样性的机制的研究也应该增加对抗菌素耐药性传播的理解，这是治疗幽门螺杆菌的一个日益严重的临床问题，从而推动NIAID了解和治疗传染病的使命。

DESCRIPTION (provided by applicant): Helicobacter pylori chronically infect 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 cancers. All H. pylori associated diseases depend on the ability of this organism to establish a persistent infection and induce chronic inflammation. Thus 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 we study genetic variation among isolates from human clinical populations. Work in previous funding periods established tools and methods necessary to take a functional genomic approach to define molecular mechanisms of pathogenesis for this organism, which is evolutionary distant from better studied enteric pathogens, including whole genome sequencing, in vivo colonization screens, and both random and an ordered sequence defined mutant libraries. Convergence of our genetic and population-based studies drives the focus of our proposed studies on DNA repair, uptake and genetic diversification as well as cell envelope proteins that appear to influence host responses. This will be accomplished in three Aims that: 1. Evaluate DNA repair as a target for H. pylori eradication therapy, 2. Explore the mechanisms and consequences of genetic variation during transmission and chronic infection, both in humans and a mouse stomach colonization model, and 3. Perform functional analysis of bacterial factors that promote and inhibit infection. Our study of the genes contributing to virulence will identify the mediators of persistent infection and studies of genetic variation in te clinical population will show how these mediators adapt during the 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, thus advancing the mission of NIAID to understand and treat infectious diseases.