E COLI PATHOGENICITY ISLANDS

性状（改编自申请人摘要）：大肠埃希菌是 医院感染的主要原因之一。 每年费用 据估计，仅在美国， 亿美元 E.大肠杆菌也是社区最常见的原因 获得性尿路感染导致估计800万 美国每年的医生访问量。 物理和遗传图谱将是 由两个大的，大约107个酶对（每个）元件构成 （致病性岛，PAI）从E.大肠杆菌J 96。 PAI代表插入 尿致病性E.大肠杆菌染色体。 PAI不是 通常存在于正常粪便E.大肠杆菌分离株或E.杆菌 K-12 有待检验的主要假设是， E.大肠杆菌肠外感染， 如肾盂肾炎和脓毒症与PAI相关。 这一假设 是基于在其他病毒中看到的毒力基因块的一般模式。 病原体和本提案中提供的初步数据。 DNA序列 对这两个PAI的分析提供了与以前的显著匹配， 特征毒力基因和移动的遗传元件， 其它病原体如沙门氏菌、志贺氏菌、耶尔森氏菌、肠致病性E. 大肠杆菌属、弧菌属、嗜血杆菌属、博德特氏菌属、假单胞菌属、沙雷氏菌属和 链球菌。 DNA序列分析是通过 与一家商业公司，人类基因组科学（HGS）合作。 的 这项建议的具体目标是：1。 构建J 96等位基因敲除 至少有八个潜在的毒力决定因素， 然后在上行尿路的小鼠模型中测试这些突变体 感染和腹膜炎; 2. 独立评估 转座子诱变和无毒突变体的阴性选择 其他PAI基因和潜在毒力基因定位的意义 泌尿系致病性大肠杆菌基因组中的其他地方。大肠杆菌; 3. 来执行分子 病原菌新毒力基因的流行病学调查 肠杆菌科的成员。 拟议的长期目标 项目的目的是建立一个完整的大肠杆菌毒力基因数据库。 大肠杆菌与严重的人类疾病有关。 这些信息将是有用的 用于开发新的化疗和疫苗策略。

DESCRIPTION (Adapted from the applicant's abstract): Escherichia coli is one of the leading causes of hospital-acquired infections. The annual cost of nosocomial infections in the U.S. alone is estimated to be in excess of 7 billion dollars. E. Coli is also the most common cause of community acquired urinary tract infection resulting in an estimated 8 million physician visits per year in the U.S.. Physical and genetic maps will be constructed of two large, approximately 107 kilobase pair (each) elements (Pathogenicity Islands, PAIs) from E. Coli J96. PAIs represent insertions within tRNA genes of uropathogenic E. Coli chromosomes. The PAIs are not commonly found in the genomes of normal fecal E. Coli isolates or E. Coli K-12. The principal hypothesis to be tested is that virulence genes responsible for the pathogenesis of E. Coli extra intestinal infections, such as pyelonephritis and sepsis are linked within PAIs. This hypothesis is based on the general pattern of virulence gene blocks seen in other pathogens and the preliminary data presented in this proposal. DNA sequence analysis of the two PAIs provide significant matches to previously characterized virulence genes and mobile genetic elements recognized in other pathogens, such as Salmonellas, Shigella, Yersinia, enterotoxigenic E. Coli, Vibrio, Haemophilus, Bordetella, Pseudomonas, Serratia and Streptococcus. The DNA sequence analysis is being performed through collaboration with a commercial company, Human Genome Sciences (HGS). The specific aims of this proposal are: 1. to construct J96 allelic knock-outs of at least eight of the potential virulence determinants identified thus far and then test these mutants in murine models of ascending urinary tract infection and peritonitis; 2. to independently assess by signature-tagged transposon mutagenesis and negative selection of avirulent mutants the significance of other PAI-genes and potential virulence genes located elsewhere in the genome for uropathogenic E. Coli; 3. to perform molecular epidemiological investigations of the new virulence genes among pathogenic members of the Enterobacteriaceae. The long term objective of the proposed project is to create a comprehensive data base of virulence genes for E. Coli involved in serious human diseases. This information will be of use for the development of new chemotherapeutic and vaccine strategies.