Understanding the role of inflammation, fibrinogen and neutrophils in persistence of E. faecalis during CAUTI

描述（由申请方提供）：导管相关尿路感染（CUTI）是最常见的医院感染之一，如果不治疗，可导致严重并发症，包括菌血症和死亡。粪肠球菌（Enterococcus faecalis）是肠道感染的主要病原体之一，由于其在医院环境中传播、在导管和其他留置医疗器械上粘附和形成生物膜的能力，以及其对多种抗生素的固有和获得性耐药性，其治疗变得越来越困难。由于对EPTI发病机制的分子细节了解不多，因此限制了预防和治疗这种感染的新疗法的开发。在一个复制了人类临床膀胱炎的许多方面的膀胱炎小鼠模型中，我们已经表明导尿管插入会引起膀胱炎症、水肿、炎性细胞因子的产生和中性粒细胞的募集，而矛盾的是，它提供了一个膀胱环境，在这个环境中，E.粪便菌可以茁壮成长我已经发现，宿主纤维蛋白原（Fg），这是释放后导管诱导的炎症，是至关重要的E。粪便粘附于导管，并促进膀胱内导管上的生长和生物膜形成。这些发现表明，操纵宿主炎症环境，以限制炎症和/或纤维蛋白原释放到膀胱腔导管插入术后可能是一种有效的策略，大大降低膀胱炎的发病率。此外，虽然Fg似乎促进E. Fg是由IL-1、IL-6和TNFα诱导的促炎分子，它与多种人类炎症性疾病有关。这就提出了E.粪肠球菌能够利用发炎的膀胱环境并抵抗宿主防御机制以定殖于插入导管的膀胱。此外，嗜中性粒细胞是最丰富的免疫细胞在ESTTI和尽管他们的存在E。粪便能够在膀胱中持续存在。目前尚不清楚为什么中性粒细胞不能完全清除感染。一些报道已经表明，Fg结合到中性粒细胞，抑制细胞凋亡途径，这对于细菌吞噬和清除以及炎症的消退是重要的。因此我推测在这期间。faecalis利用由于对导管插入的炎症反应而释放纤维蛋白原以持续和规避中性粒细胞杀菌功能，并且限制炎症将减少E.粪球菌本论文的第一个目的是研究炎症细胞因子对膀胱内Fg释放和积聚的影响，以及它们在大肠杆菌中的作用。粪持续性我的第二个目标是研究纤维蛋白原在调节中性粒细胞活性中的作用，以及这种相互作用对E。粪便免疫逃避。E.粪便-宿主相互作用机制是理解ESTI病理生理学所必需的，以揭示有效预防宿主炎症和治疗E.粪便感染这些结果对于需要急性或长期导管插入的患者具有重要意义。

DESCRIPTION (provided by applicant): Catheter-associated urinary tract infections (CAUTIs) are one of the most common nosocomial infections and if untreated can lead to serious complications including bacteremia and death. Enterococcus faecalis is one of the leading causative agents of CAUTI and its treatment has become increasingly difficult due to its ability to disseminate in hospital settings, adhere and form biofilms on catheters and other indwelling medical devices, and its inherent and acquired resistance to multiple antibiotics. The poor understanding of the molecular details of CAUTI pathogenesis has limited the development of new therapies to prevent and treat this infection. In a mouse model of CAUTI, which replicates many aspects of human clinical CAUTI, we have shown that urinary catheterization elicits bladder inflammation, edema, production of inflammatory cytokines, and neutrophil recruitment, while paradoxically, providing a bladder environment in which E. faecalis can thrive. I have found that host fibrinogen (Fg), which is released upon catheter-induced inflammation, is critical for E. faecalis adherence to catheters and for promoting growth and biofilm formation on catheters within the bladder. These findings suggest that manipulating the host inflammatory environment to limit inflammation and/or Fg release into the bladder lumen upon catheterization may be an effective strategy to greatly reduce the incidence of CAUTI. Further, while Fg seems to promote E. faecalis infection in CAUTI, in other systems it has been shown that Fg is a proinflammatory molecule that is induced by IL-1, IL-6, and TNFα it is linked to multiple human inflammatory diseases. This raises additional questions of how E. faecalis is able to exploit the inflamed bladder environment and withstand host defense mechanisms to colonize the catheterized bladder. Furthermore, neutrophils are the most abundant immune cells during CAUTI and despite their presence E. faecalis is able to persist in the bladder. It is unclear why neutrophils are unable to completely clear the infection. Several reports have shown that Fg binds to neutrophils suppressing the apoptosis pathway, which is important for bacterial phagocytosis and clearance, and for resolution of the inflammation. Therefore I hypothesize that during CAUTI E. faecalis exploits the release of fibrinogen due to the inflammatory response to catheterization for persistence and for circumvention of neutrophil bactericidal function and that limiting inflammation will decrease E. faecalis CAUTI. My first Aim will investigate the contribution of inflammatory cytokines to the release and accumulation of Fg in the bladder and their role in E. faecalis persistence. My second Aim will examine the role of Fg in modulating neutrophil activity and the contribution of this interaction to E. faecalis immune evasion during CAUTI. Elucidation of E. faecalis-host interaction mechanisms is needed to understand CAUTI pathophysiology in order to uncover possible strategies to efficiently prevent host inflammation and treat E. faecalis infection. These results will be of significant importance for patients that require acute or prolonged catheterization.