Reciprocal Control of Motility and Adherence in UTI

描述（由申请人提供）：尿路是一个复杂的上皮衬里管，具有通向体表的开口，使其容易受到外源性微生物的感染。事实上，尿路感染是人类最常见的细菌感染之一，也是美国最常见的肾脏和泌尿系统疾病。最常见的尿路病原体大肠杆菌可在无并发症的尿路中引起急性膀胱炎或肾盂肾炎。另一方面，在患有复杂尿路的患者中，其中正常尿流被结构异常或导尿管阻塞，奇异变形杆菌等物种占主导地位。E.大肠杆菌和奇异变形杆菌是肠杆菌科的成员，是能动的，并产生一组菌毛，通过菌毛介导对尿路上皮的粘附。利用鞭毛游动和通过某些菌毛粘附的能力已被证明是这两种生物的毒力特征。然而，这两种细胞器的行为具有相反的功能。我们的理由是，有一个时间游泳和时间坚持，我们还提供了初步的数据，E。大肠杆菌和奇异变形杆菌具有明确的调控途径，通过这些途径它们从运动型转化为粘附型，反之亦然。此外，还发现了其他监管机制。在这个建议中，我们将测试的中心假设，尿路致病性大肠杆菌。大肠杆菌和奇异变形杆菌调节运动性和粘附性之间的平衡。我们将通过实现以下具体目标来检验这一假设：1）确定运动性和粘附性的相互控制机制; 2）确定鞭毛和菌毛表达的其他机制，包括协调表达、选择和生长阶段的调节; 3）在体内证明运动性和粘附性的控制。遗传结构，分子检测，微阵列，和上行性尿路感染的小鼠模型将被用来测试的假设。确定一个明确的机制的影响远远超出了泌尿道。显然，在呼吸道、肠道和生殖道的粘膜表面定殖的能力也需要用于粘附的菌毛和用于运动的鞭毛的协调合成。

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 one of the most common bacterial infections of humans and the most common kidney and urologic disease in the U.S. The most common uropathogen, Escherichia coli, can cause 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 are blocked by structural abnormality or urethral catheters, species such as Proteus mirabilis 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. We reason that there is a time to swim and a time to adhere; we also provide preliminary data that E. coli and P. mirabilis possess defined regulatory pathways by which they transform from the motile to the adherent form and wee versa. As well, other regulatory mechanisms have been uncovered. In this proposal, we will test the central hypothesis that uropathogenic E. coli and P. mirabilis regulate the balance between motility and adherence. We will test this hypothesis by carrying out the following specific aims: 1) Determine the mechanism of reciprocal control of motility and adherence; 2) Determine other mechanisms of flagella and fimbriae expression including coordinated expression, selection, and regulation by growth phase; and 3) Demonstrate in vivo the control of motility and adherence. Genetic constructs, molecular assays, microarrays, and a murine model of ascending urinary tract infection will be used to test the hypothesis. Determination of a defined mechanism has implications far beyond the urinary tract. Clearly the ability to colonize mucosal surfaces in the respiratory, intestinal, and genital tracts also require the orchestrated synthesis of fimbriae for adherence and flagella for motility.