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

描述（由申请人提供）：导尿管相关性尿路感染（CAUTIs）是最常见的医院感染之一，如果不治疗可导致严重的并发症，包括菌血症和死亡。粪肠球菌是CAUTI的主要病原体之一，由于其能够在医院环境中传播，在导管和其他留置医疗器械上粘附并形成生物膜，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。对CAUTI发病机制的分子细节了解不足，限制了预防和治疗这种感染的新疗法的发展。在一个复制了人类临床CAUTI许多方面的小鼠CAUTI模型中，我们已经表明，导尿引起膀胱炎症、水肿、炎症细胞因子的产生和中性粒细胞的募集，同时矛盾的是，提供了一个粪肠杆菌可以茁壮成长的膀胱环境。我发现宿主纤维蛋白原（Fg）在导管诱导炎症时被释放，对于粪肠杆菌粘附在导管上以及促进膀胱内导管的生长和生物膜形成至关重要。这些发现表明，通过控制宿主炎症环境来限制炎症和/或Fg释放到膀胱腔中，可能是大大降低CAUTI发病率的有效策略。此外，虽然Fg似乎在CAUTI中促进粪肠球菌感染，但在其他系统中，Fg是一种由IL-1、IL-6和tnf - α诱导的促炎分子，它与多种人类炎症性疾病有关。这就提出了更多的问题，即粪肠球菌如何能够利用发炎的膀胱环境并抵御宿主的防御机制来殖民导管膀胱。此外，中性粒细胞是CAUTI期间最丰富的免疫细胞，尽管它们存在，粪肠球菌仍能在膀胱中持续存在。目前尚不清楚为什么中性粒细胞不能完全清除感染。一些报道表明，Fg与中性粒细胞结合抑制细胞凋亡途径，这对于细菌吞噬和清除以及炎症的解决是重要的。因此，我假设在CAUTI期间，粪肠球菌利用纤维蛋白原的释放，这是由于对导管的炎症反应造成的，以维持和规避中性粒细胞的杀菌功能，并且限制炎症将减少粪肠球菌的CAUTI。我的第一个目标是研究炎性细胞因子对膀胱中Fg的释放和积累的贡献及其在粪肠球菌持久性中的作用。我的第二个目标是研究Fg在调节中性粒细胞活性中的作用，以及这种相互作用对CAUTI期间粪肠球菌免疫逃避的贡献。阐明粪肠球菌与宿主的相互作用机制是了解CAUTI病理生理的必要条件，从而揭示有效预防宿主炎症和治疗粪肠球菌感染的可能策略。这些结果对于需要急性或长期置管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.