Molecular mechanisms of uropathogenesis

尿路发病的分子机制

• 批准号: 8886834
• 负责人: HARRY L. MOBLEY
• 金额: $ 20.71万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886834
• 关键词: Acute Cystitis; Adherence; Agar; Area; Bacteremia; Bacteria; Bacterial Adhesins; Bacterial Infections; Biology; Birth; Bladder; Bladder Calculi; Body Surface; Calculi; Carbohydrates; Catheters; Cells; Colon; Deformity; Development; Enterobacteriaceae; Epithelial; Escherichia coli; Flagella; Foreign Bodies; Funding; Gene Expression Profile; Genes; Grant; Homologous Gene; Hospitals; Human; Immobilized Cells; Individual; Infection; Investigation; Iron; Kidney; Kidney Calculi; Kidney Diseases; Knowledge; Life; Life Style; Mediating; Mirabilis; Molecular; Mucous body substance; Newborn Infant; Obstruction; Operon; Organelles; Organism; Outcome; Patients; Phase; Phenotype; Physicians; Property; Proteins; Proteus mirabilis; Public Health; Reflux; Regulator Genes; Regulatory Pathway; Reporting; Repression; Research; Respiratory Tract Infections; Rest; Site; Social Behavior; Structural defect; Surface; Swimming; Symptoms; System; Testing; Time; Toxin; Tube; United States; Ureter; Urethra; Urinary tract; Urinary tract infection; Urination; Urine; Urologic Diseases; Uropathogen; Uropathogenic E. coli; Vaccines; Virulence; Virulent; Visit; Woman; acute pyelonephritis; antimicrobial; antimicrobial drug; cell motility; combat; cost; fimbria; fitness; gene repression; killings; mannose-resistant Proteus-like (MR/P) fimbria; member; novel; pathogen; pressure; public health relevance; receptor; renal scarring; trait; urinary; urolithiasis

 DESCRIPTION (provided by applicant): The urinary tract is a complicated epithelial-lined tube with an opening to the body surface, making it susceptible to infection by exogenous organisms. Indeed, urinary tract infection is the second most common bacterial infection of humans and the most common kidney and urologic disease in the U.S. The most common uropathogen, Escherichia coli, causes acute cystitis or pyelonephritis in the uncomplicated urinary tract. On the other hand, in patients with complicated urinary tracts, ones in which normal urine flow is blocked by structural abnormality or urethral catheters, Proteus mirabilis may predominate. Both E. coli and P. mirabilis are members of the Enterobacteriaceae, are motile, and produce a battery of fimbriae by which they mediate adherence to the uroepithelium. The abilities to swim using flagella and to adhere by certain fimbriae have been demonstrated to be virulence traits for both organisms. However the actions of the two organelles have opposite functions and should not be employed at the same time. We have provided significant evidence and developed the theme that E. coli and P. mirabilis possess defined regulatory pathways by which they transition from the adherent to the motile form and display unique phenotypes associated with each lifestyle. Genes expressed during these opposite lifestyles govern the biology of infection of the urinary tract. Terminal genes in adherence gene operons of both pathogens have been demonstrated to specifically repress motility. However, when these phase variable fimbrial operons are in the off phase, flagella are expressed. In P. mirabilis, MrpJ (a PapX homolog) encoded by the MR/P fimbrial operon, inhibits swarming. When MR/P fimbriae are phase off, P. mirabilis differentiates into highly motile swarmer cells and induces a type 6 secretion system to kill competitors. In E. coli, the P fimbrial operon gene product PapX and the non-fimbrial TosA operon gene products TosE and TosF repress flagellar synthesis. These compelling phenotypes will be the subject of investigation. In this proposal, we will advance the central hypothesis that uropathogenic E. coli and P. mirabilis regulate adherence and motility resulting in distinct patterns of gene expression that are advantageous during infection of the urinary tract. We will test this hypothesis by carrying out the following specific aims: 1) Determine the mechanism of interbacterial killing by the swarming-induced type VI secretion system in Proteus mirabilis. 2) Determine the mechanism of repression of motility by regulatory genes in the pap and tos adherence operons in uropathogenic E. coli. This contribution will be significant because two of the principal virulence properties of E. coli and P. mirabilis are adherence and motility. Understanding the mechanisms by which these species regulate these critical traits and defining the phenotypes associated with each phase will advance our knowledge of these pathogens. By implementing our specific aims, we will elucidate regulatory pathways that govern two critical functions, motility and adherence, which will provide the opportunity to identify novel targets for development of new antimicrobial agents.

 描述（由适用提供）：尿路是一种复杂的上皮管，并向身体表面开口，使其容易受到外源性生物感染的影响。实际上，泌尿道感染是人类的第二大最常见细菌感染，是美国最常见的肾脏病和泌尿科疾病，是最常见的尿路疾病，大肠杆菌，可引起急性膀胱炎或肾上腺炎，在不复杂的尿道中。另一方面，在复杂的尿路患者中，正常尿液流动被结构异常或尿道导管阻塞的患者，proteus mirabilis可能占主导地位。大肠杆菌和小疟原虫都是肠杆菌科的成员，是运动的，并且产生了一堆薄膜，它们可以介导对近去的粘附。已经证明，使用鞭毛并通过某些fimbriae粘附游泳的能力已被证明是两种生物的病毒特征。但是，两个细胞器的作用具有相反的功能，不应同时雇用。我们提供了大量证据，并开发了一个主题，即大肠杆菌和奇异疟原虫具有定义的调节途径，它们从粘附形式过渡到基序形式，并显示与每种生活方式相关的独特表型。在这些相反的生活方式中表达的基因控制着尿路感染的生物学。两种病原体的粘附基因操纵子中的末端基因已被证明特异性反映了运动。但是，当这些相变纤维操纵子处于离阶段时，鞭毛会表达。在Mirabilis的P. mirabilis中，由MR/P纤维操纵子编码的MRPJ（一个PAPX同源物）抑制蜂群。当MR/p纤维膜分阶段关闭时，P. mirabilis会区分高度运动的蜂群，并诱导6型分泌系统杀死竞争者。在大肠杆菌中，P膜片操纵子基因产物PAPX和非纤维状TOSA操纵子基因产物Tose和TOSF抑制鞭毛合成。这些引人注目的表型将是研究的主题。在此提案中，我们将推进一个中心假设，即尿液发育性大肠杆菌和小假单胞菌调节了粘附和运动，从而产生了不同的基因表达模式，这些模式在尿道感染过程中具有优势。我们将通过执行以下特定目的来检验这一假设：1）确定由Proteus mirabilis中的蜂群诱导的VI型分泌系统杀死细菌间杀死的机制。 2）确定调节基因在子宫颈瘤和肌病大肠杆菌中粘附操纵子中通过调节基因表达的机理。这种贡献将是重要的，因为大肠杆菌和奇异疟原虫的两个主要病毒特性是依从性和运动性。了解这些物种调节这些关键特征并定义与每个阶段相关的表型的机制将提高我们对这些病原体的了解。通过实施我们的具体目标，我们将阐明管理两个关键功能的运动和依从性，这将为确定新的抗微生物剂的新目标提供机会。