Control of bladder infections by NF-kappaB

描述(申请人提供)：尿路感染，包括膀胱炎和肾盂肾炎，是人类感染的最常见的传染病之一。这些感染在全世界造成了相当大的发病率、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有强烈的复发趋势。绝大多数尿路感染是由能结合和侵袭膀胱上皮细胞的尿路致病性大肠杆菌(UPEC)引起的。在膀胱细胞内，UPEC要么增殖，要么进入非复制的持续静止状态，这可能是未来反复发生的急性感染的蓄水池。细胞内的UPEC受到标准抗生素治疗的保护，这些治疗可以有效地消毒尿液。此外，UPEC分离株对多种抗生素的耐药性正变得越来越普遍，进一步限制了目前尿路感染治疗方案的有效性。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侵袭膀胱上皮细胞、细胞内增殖和从宿主细胞中重新出现的能力。核因子-kappaB调节许多宿主基因的转录，包括许多与促炎反应相关的基因，这些反应有助于限制感染。然而，我们的初步数据表明，UPEC需要NF-kappaB活性才能有效地在宿主膀胱上皮细胞内定植和持续存在，这是一种违反直觉的可能性。该R21应用的主要目的是确定核因子-kappaB作为UPEC发病的调节因子和潜在促进剂的作用。此外，我们将通过建立一个成熟的小鼠膀胱炎模型，测试一种核因子-kappaB抑制剂在治疗和预防急性和复发性膀胱炎方面的治疗潜力。

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.