Molecular Clonality of Uropathogenic E. Coli

描述（由申请人提供）：我们的长期目标是在分子水平上促进对尿路致病性大肠杆菌（UPEC）菌株的致病性和流行病学的理解，以更好地靶向治疗和预防尿路感染，减少耐药性，并提供疫苗和抗生素可能靶点的信息。因此，对大肠杆菌尿毒力机制的研究将是今后研究的重点。大肠杆菌的全基因组比较分析菌株，将从大量的首次和复发性膀胱炎患者和健康妇女分离。核心假设是，相对较少的克隆组参与UPEC人类发病机制可以定义和表征其关键的遗传基因座和遗传变异对UPEC毒力的影响。我们的初步数据支持我们可以研究新鲜分离株的相当大的样本，建立与复发性膀胱炎的强克隆关联，并确定全基因组的致病性适应性遗传变化。我们将确定突变变化（单核苷酸多态性，小插入/缺失等）和水平基因转移如何促成UPEC的出现。我们的目标是潜在地检查至少一部分UPEC菌株所共有的每个基因，以确定是否处于致病性适应性突变或水平转移的正选择下。为此，我们将采用基于群体基因组学的分析来追踪突变和基因转移，然后评估UPEC中代表性阳性选择位点的功能意义。

DESCRIPTION (provided by applicant): Our long-term goal is to advance the understanding, at the molecular level, of the pathogenicity and epidemiology of uropathogenic Escherichia coli (UPEC) strains to better target treatment and prophylaxis of urinary tract infections, reduce resistance, and provide information on possible targets for vaccines and antibiotics. The proposed studies are focused on understanding the basis of urovirulence of E. coli by the comparative genome-wide analysis of strains that will be isolated from a large number of patients with first-time and recurrent cystitis and healthy women. The central hypothesis is that the relatively few clonal groups involved in UPEC human pathogenesis can be defined and characterized as to their key genetic loci and the impact of genetic variations on UPEC virulence. Our preliminary data support that we can investigate sizeable samples of fresh isolates, establish strong clonal associations with recurrent cystitis and determine genome- wide the pathogenicity-adaptive genetic changes. We will determine how mutational changes (single nucleotide polymorphisms, small insertions/deletions, etc) and horizontal gene transfer contribute to the emergence of UPEC. Our aim is to potentially examine every gene shared by at least a portion of UPEC strains for being under positive selection for pathogenicity-adaptive mutations or horizontal transfer. For this, we will employ a population genomics-based analysis to trace the mutations and gene transfer, followed by assessment of the functional significance of the representative positively selected loci in UPEC.