Control of bladder infections by NF-kappaB

描述（由申请人提供）：尿路感染，包括膀胱炎和肾盂肾炎，是人类获得的最常见的传染病之一。这些感染在全世界造成大量发病率、死亡率和高昂的医疗费用。这些感染的一个特别麻烦的方面是它们强烈的复发倾向。绝大多数尿路感染是由尿路致病性大肠杆菌（UPEC）菌株引起的，它可以结合并侵入膀胱上皮细胞。在膀胱细胞内，UPEC要么繁殖，要么进入不复制的持续静止状态，这可能成为未来复发性急性感染的储存库。细胞内UPEC不受标准抗生素治疗的影响，可以有效地对尿液进行消毒。此外，UPEC分离株对多种抗生素的耐药性正变得越来越普遍，进一步限制了当前尿路感染治疗方案的疗效。利用细胞培养模型系统，我们最近发现宿主转录因子NF-kappaB的抑制剂能够有效地干扰UPEC侵入膀胱上皮细胞、细胞内繁殖和从宿主细胞中再生的能力。NF-kappaB调节许多宿主基因的转录，包括许多与抑制感染的促炎反应相关的基因。然而，我们的初步数据表明，与直觉相反，NF-kappaB活性是UPEC有效定植和持续存在于宿主膀胱上皮细胞中的必要条件。本R21应用的主要目的是确定NF-kappaB作为UPEC发病机制的调节因子和潜在促进因子的作用。此外，我们将通过建立小鼠膀胱炎模型来测试NF-kappaB抑制剂在治疗和预防急性和复发性膀胱感染方面的治疗潜力。

DESCRIPTION (provided by applicant): Urinary tract infections, including cystitis and pyelonephritis, are among the most common of infectious diseases acquired by humans. These infections are responsible for substantial morbidity, mortality and high medical costs worldwide. An especially troublesome aspect of these infections is their strong tendency to recur. The vast majority of urinary tract infections are caused by strains of uropathogenic Escherichia coil (UPEC) that can bind and invade bladder epithelial cells. Within bladder cells, UPEC will either multiply or enter a non-replicating, persistent quiescent state that may serve as a reservoir for future recurrent acute infections. Intracellular UPEC is protected against standard antibiotic treatments that can effectively sterilize the urine. In addition, resistance to multiple antibiotics among UPEC isolates is becoming increasingly widespread, further limiting the efficacy of current treatment protocols for urinary tract infections. Using a cell culture model system, we recently found that inhibitors of the host transcription factor NF-kappaB are able to effectively interfere with the ability of UPEC to invade bladder epithelial cells, multiply intracellularly and reemerge from the host cells. NF-kappaB regulates the transcription of a number of host genes, including many associated with pro-inflammatory responses that work to limit infections. Our preliminary data, however, suggest the counterintuitive possibility that NF-kappaB activity is required for UPEC to effectively colonize and persist within host bladder epithelial cells. The primary Aim of this R21 application is to define the role of NF-kappaB as a regulator and potential facilitator of UPEC pathogenesis. In addition, we will test the therapeutic potential of a NF-kappaB inhibitor in the treatment and prevention of both acute and recurrent bladder infections using a well-established mouse cystitis model.