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

了解炎症、纤维蛋白原和中性粒细胞在 CAUTI 期间粪肠球菌持续存在中的作用

• 批准号: 8835481
• 负责人: Ana Lidia Flores-Mireles
• 金额: $ 5.33万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835481
• 关键词: Acute; Adherence; Antibiotic Resistance; Antibiotics; Antibodies; Apoptosis; Attenuated; Bacteremia; Bacteria; Bacterial Adhesins; Behavior; Binding; Bladder; Bladder Tissue; C57BL/6 Mouse; Catheterization; Catheters; Cells; Cessation of life; Clinical; Data; Defense Mechanisms; Deposition; Development; Dexamethasone; Diagnosis; Disease; Edema; Enterococcus; Enterococcus faecalis; Environment; Europe; Fibrin; Fibrinogen; Functional disorder; Growth; Health; Hospitals; Host Defense Mechanism; Human; IL6 gene; Immune; In Vitro; Incidence; Incubated; Individual; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-12; Interleukin-17; Interleukin-6; Invaded; Lead; Link; Macrophage-1 Antigen; Medical Device; Microbial Biofilms; Microscopy; Mole the mammal; Molecular; Morbidity - disease rate; Mus; Neutrophil Infiltration; Nosocomial Infections; Outcome; Pathogenesis; Pathway interactions; Patients; Phagocytosis; Pilum; Production; Recruitment Activity; Reporting; Resistance; Resolution; Risk; Role; Signal Transduction; Staining method; Stains; System; Testing; Tumor Necrosis Factor-alpha; United States; Urinary Catheterization; antibody inhibitor; bactericide; catheter associated UTI; cytokine; effective therapy; implantation; insight; interdisciplinary approach; killings; mortality; mouse model; mutant; neutrophil; novel; pathogen; prevent

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.

描述（由适用提供）：与导管相关的尿路感染（CAUTIS）是最常见的医院感染之一，如果未治疗，可能会导致严重的并发症，包括细菌和死亡。粪肠球菌是Cauti的主要严重药物之一，由于其在医院环境，粘附并在导管和其他留置医疗设备上粘附并形成生物膜的能力，其治疗变得越来越困难。对CAUTI发病机理的分子细节的不良理解限制了预防和治疗这种感染的新疗法的发展。在复制人类临床Cauti的许多方面的小鼠模型中，我们表明，尿管插入术会引起膀胱感染，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，在这种情况下提供了大叶口球的膀胱环境。我发现，在导管诱导的感染时释放的宿主纤维蛋白原（FG）对于粪肠球菌遵守导管和促进膀胱内导管上的生长和生物膜形成至关重要。这些发现表明，操纵宿主炎症环境以在导管插入后限制膀胱腔内的感染和/或FG释放可能是一种有效降低Cauti发生率的有效策略。此外，虽然FG似乎促进了CAUTI中的粪肠球菌感染，但在其他系统中，FG是由IL-1，IL-6和TNFα诱导的促炎分子，它与多种人类炎性疾病有关。这就提出了其他问题，即E. Faecalis如何能够探索发炎的膀胱环境并承受宿主防御机制，以殖民导管刀片。此外，嗜中性粒细胞是尾ta期间最丰富的免疫细胞，它们的存在E.粪便能够持续在膀胱中。目前尚不清楚为什么中性粒细胞无法完全清除感染。几份报告表明，FG与抑制凋亡途径的中性粒细胞结合，这对于细菌吞噬和清除率以及注射的分辨率很重要。因此，我假设在小肠球菌期间，由于对导管插入术的持续性和抑制嗜中性粒细胞杀菌功能的炎症反应，纤维蛋白原的释放会释放，并且限制炎症会降低粪肠球菌。我的第一个目的将研究炎症细胞因子对膀胱中FG释放和积累的贡献及其在粪肠球菌持久性中的作用。我的第二个目标将研究FG在调节中性粒细胞活性的作用以及这种相互作用对肠球菌中粪肠球菌免疫进化的贡献。需要阐明粪肠球菌 - 宿主 - 宿主相互作用机制，以了解CAUTI病理生理学，以发现可能的策略以有效防止宿主感染和治疗粪肠球菌感染。对于需要急性导管插入术的患者，这些结果将非常重要。