Understanding the role of catheter-associated protein deposition in the development of CAUTI

了解导管相关蛋白沉积在 CAUTI 发展中的作用

• 批准号: 10205909
• 负责人: Ana Lidia Flores-Mireles
• 金额: $ 36.53万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10205909
• 关键词: Accounting; Acinetobacter; Adhesions; Affect; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteremia; Bacteria; Bacterial Infections; Binding; Binding Proteins; Biomedical Engineering; Bladder; Candida; Candida albicans; Catheterization; Catheters; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Data; Deposition; Development; Devices; Disease; Disease Progression; Edema; Elements; Enterococcus; Enterococcus faecalis; Environment; Epithelial; Escherichia coli; Exhibits; Fibrinogen; Foundations; Frequencies; Functional disorder; Goals; Healthcare; Histologic; Host Defense; Hour; Human; Immobilization; Immune; Immune response; Immunologics; Implant; In Vitro; Infection; Infiltration; Inflammation; Inflammatory Response; Intervention; Klebsiella pneumoniae; Knowledge; Life Style; Liquid substance; Mechanical Stress; Mechanics; Medical; Medical Device; Microbial Biofilms; Modernization; Modification; Mus; Nosocomial Infections; Organism; Outcome; Pathogenesis; Pathologic; Patients; Positioning Attribute; Procedures; Process; Proteins; Proteomics; Proteus mirabilis; Pseudomonas aeruginosa; Publishing; Quality of life; Research; Resistance; Role; Silicones; Silver; Staphylococcus aureus; Surface; Systemic infection; Testing; Thinness; Tissues; Urinary Catheterization; Urinary tract; Urinary tract infection; Uropathogen; Water; Work; aging population; alternative treatment; antimicrobial; base; biomaterial interface; catheter associated UTI; cohesion; cytokine; design; drug resistant pathogen; experimental study; healing; healthcare-associated infections; improved; in vitro testing; in vivo; insight; methicillin resistant Staphylococcus aureus; microbial; microbial colonization; microbial host; mouse model; novel; pathogen; pathogenic microbe; prevent; response; surface coating; urinary

PROJECT SUMMARY: Modern healthcare has implemented medical devices to help and improve the life quality of people with chronic and lifestyle diseases. Paradoxically, although these devices are successful in achieving their purpose, they make the patient susceptible to infections. Urinary catheters are among the most widely used medical devices, and currently, catheter-associated urinary tract infections (CAUTI) are the most common healthcare-associated infection (HAI) worldwide, accounting for 40% of all HAIs. In addition, the treatment and control of CAUTI is becoming increasingly challenging due to the rise of antibiotic-resistant pathogens. Critically, CAUTIs are very different from uncomplicated urinary tract infections (UTIs), exhibiting unique clinical and pathological manifestations, as well as causative organisms. For example, in uncomplicated UTI, E. coli accounts for >95% of the causative agent, whereas in CAUTI, urinary catheterization allows pathogens such as Enterococcus spp., Staphylococcus aureus, Candida spp., Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumanii to colonize the bladder, something that otherwise would not occur. Given that the frequency of catheter usage is only expected to increase due to both an aging population and medical advances, it is imperative to understand the pathophysiology of CAUTI if we are to develop ways to treat and/or prevent it. Recent work has found that urinary catheterization elicits bladder inflammation and mechanically disrupts the host defenses, compromising the host for microbial colonization. Further findings in mice and humans have shown that fibrinogen (Fg) is released and accumulated in the bladder to heal the damaged tissue. Fg is also deposited on catheters, coating them and forming a platform for colonization by CAUTI-associated pathogens. It was found that Fg levels modulate outcome of the infection and, in the absence of Fg, E. faecalis is unable to stick to the catheter and colonize the bladder. On the other hand, high Fg levels enhance enterococcal bladder and catheter colonization. This suggests that protein deposition on urinary catheters is a key factor for microbial infection. This proposal tests the hypothesis that by controlling the amount of protein deposition on the surface using a novel liquid surface coating, we will be able to control the rate and extent of uropathogen biofilm formation, urinary tract colonization, and systemic dissemination, as well as the inflammation response. Through a combination of material modification, proteomics, histological, and immunological approaches with a mouse model of CAUTI, we will: 1) develop liquid-infused catheters that control protein deposition; 2) assess their contribution in reducing protein deposition and biofilm formation in vitro; and 3) characterize in vivo how protein deposition modulation affects biofilm formation, the outcome of infection, and inflammation. Understanding the role of protein deposition in promoting pathogen-material-host interactions will provide new perspective in the establishment and progression of CAUTI, generating key insights into the development of alternative treatments that do not contribute to microbial resistance.

项目摘要：现代医疗实施医疗器械助力和提高生活质量 患有慢性病和生活方式疾病的人。矛盾的是，尽管这些设备成功地实现了 他们的目的，他们使患者容易受到感染。导尿管是最广泛使用的导尿管之一 医疗器械，目前，导管相关性尿路感染(CAUTI)是最常见的 全球医疗保健相关感染(HAI)，占所有HAI的40%。此外，治疗和 由于抗药性病原体的增加，CAUTI的控制正变得越来越具有挑战性。关键是， CAUTIs与非复杂性尿路感染(UTIs)非常不同，表现出独特的临床和 病理表现，以及致病微生物。例如，在不复杂的尿路感染中，大肠杆菌 对于95%的病原体，而在CAUTI，导尿术允许病原体，如 肠球菌、金黄色葡萄球菌、念珠菌、奇异变形杆菌、铜绿假单胞菌和 鲍曼不动杆菌在膀胱中定植，否则就不会发生的事情。考虑到 由于人口老龄化和医学进步，导管的使用频率预计只会增加， 如果我们要开发治疗和/或预防CAUTI的方法，了解CAUTI的病理生理学是必不可少的。 最近的研究发现，导尿术会引发膀胱炎，并机械地破坏膀胱的功能 寄主防御，危害寄主微生物定植。在老鼠和人类身上的进一步发现 研究表明，纤维蛋白原(Fg)在膀胱中释放和积累，以修复受损组织。FG也是 沉积在导管上，覆盖在导管上，形成与CAUTI相关的病原体定植的平台。 研究发现，Fg水平调节感染的转归，在缺乏Fg的情况下，粪肠球菌不能 粘在导尿管上并定植于膀胱。另一方面，高水平的纤维蛋白原可增强肠球菌的膀胱。 和导管定植。这表明尿管上的蛋白质沉积是微生物的一个关键因素。 感染。这一提议验证了这样一种假设，即通过控制蛋白质在表面的沉积量 使用一种新型的液体表面涂层，我们将能够控制尿路病原体生物被膜的速度和程度。 形成、尿路定植、全身扩散以及炎症反应。穿过 材料修饰、蛋白质组学、组织学和免疫学方法与小鼠的结合 在CAUTI模型中，我们将：1)开发控制蛋白质沉积的液体输注导管；2)评估它们的 在减少体外蛋白质沉积和生物膜形成方面的贡献；以及3)在体内表征蛋白质如何 沉积调节影响生物膜的形成、感染的结局和炎症。了解 蛋白质沉积在促进病原体-物质-宿主相互作用中的作用将为研究提供新的视角 CAUTI的建立和发展，为替代治疗的发展产生关键见解 不会对微生物产生抵抗力。