Genetic Requirements of Helicobacter pylori Infection

描述（由申请人提供）：幽门螺杆菌慢性感染世界上一半的人的胃，大约三分之一的美国人口。幽门螺杆菌在所有宿主中引起炎症，10-20%的感染者会出现严重的疾病，包括消化性溃疡和胃癌。所有幽门螺杆菌相关疾病都依赖于这种有机体建立持续感染和诱导慢性炎症的能力。因此，幽门螺杆菌疾病是建立和维持感染所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，细菌和宿主在几十年的感染中都会发生变化。为了研究这一复杂的过程，我们利用小鼠感染模型，并研究了人类临床人群中分离株的遗传变异。在之前的资助阶段，建立了必要的工具和方法，采用功能基因组方法来定义这种生物的分子发病机制，这种生物与更好地研究肠道病原体的进化距离较远，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文库。我们的遗传和基于群体的研究的融合推动了我们对DNA修复、摄取和遗传多样化以及似乎影响宿主反应的细胞包膜蛋白的研究重点。这将通过三个目标来实现：1。评估DNA修复作为幽门螺杆菌根除治疗的目标，2。2 .在人类和小鼠胃定植模型中探索传播和慢性感染过程中遗传变异的机制和后果；对促进和抑制感染的细菌因子进行功能分析。我们对致病基因的研究将确定持续感染的介质，对临床人群遗传变异的研究将显示这些介质在与感染相关并导致严重疾病（溃疡、癌症）的慢性炎症期间如何适应。我们对幽门螺杆菌促进遗传交换和多样化的机制的研究也应该增加对抗菌药物耐药性传播的认识，这是幽门螺杆菌治疗中日益严重的临床问题，从而推进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.