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: 9187454
• 负责人: Ana Lidia Flores-Mireles
• 金额: $ 6.1万
• 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/9187454
• 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; Hospitals; Host Defense Mechanism; Human; IL6 gene; Immune; Immune Evasion; Impairment; In Vitro; Incidence; Incubated; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-12; Interleukin-17; Interleukin-6; Invaded; Lead; Link; Macrophage-1 Antigen; Medical Device; Microbial Biofilms; Microscopy; Molecular; Morbidity - disease rate; Mus; Neutrophil Infiltration; Nosocomial Infections; Outcome; Pathogenesis; Pathway interactions; Patients; Phagocytes; Phagocytosis; Pilum; Production; Reporting; Resistance; Resolution; Risk; Role; Signal Transduction; Staining method; Stains; System; TNF gene; Testing; United States; Urinary Catheterization; antibody inhibitor; bactericide; catheter associated UTI; cytokine; effective therapy; implantation; inflammatory milieu; insight; interdisciplinary approach; killings; mortality; mouse model; mutant; neutrophil; novel; novel therapeutics; pathogen; prevent; public health relevance

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（由申请人提供）：导管相关性尿路感染 (CAUTI) 是最常见的医院感染之一，如果不及时治疗，可能会导致严重的并发症，包括菌血症和死亡，粪肠球菌是 CAUTI 及其相关疾病的主要病原体之一。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，治疗变得越来越困难，并且对多种抗生素固有的和获得性的耐药性对 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开发。研究表明，导尿会引起膀胱炎症、水肿、炎性细胞因子的产生和中性粒细胞的募集，但矛盾的是，它提供了粪肠球菌可以繁殖的膀胱环境，我发现宿主纤维蛋白原。 (Fg) 是在导管引起的炎症时释放的，对于粪肠球菌粘附在导管上以及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限制炎症和/或。插管后将 Fg 释放到膀胱腔可能是大大降低 CAUTI 发生率的有效策略。此外，虽然 Fg 似乎会促进 CAUTI 中粪肠球菌感染，但在其他系统中已表明 Fg 是一种促进 CAUTI 感染的方法。粪肠球菌是一种由 IL-1、IL-6 和 TNFα 诱导的促炎分子，与多种人类炎症性疾病有关，这提出了粪肠球菌如何能够利用发炎的膀胱环境并抵抗宿主防御机制来定殖的其他问题。此外，中性粒细胞是 CAUTI 期间最丰富的免疫细胞，尽管存在粪肠球菌，但尚不清楚为什么中性粒细胞无法完全清除感染。已经表明，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非常重要，因此我认为，在 CAUTI 期间，粪肠球菌利用了由于导管插入的炎症反应而释放的纤维蛋白原。持久性和规避中性粒细胞杀菌功能以及限制炎症将减少粪肠球菌 CAUTI。 Fg 在膀胱中的释放和积累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粪肠球菌在 CAUTI 期间免疫逃避的贡献。 - 需要了解 CAUTI 病理生理学的宿主相互作用机制，以便发现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慢性感染的患者具有重要意义。长时间导尿。