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: 10605360
• 负责人: Ana Lidia Flores-Mireles
• 金额: $ 37.28万
• 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/10605360
• 关键词: Accounting; Acinetobacter; Adhesions; Affect; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteremia; Bacteria; Binding; Binding Proteins; Biomedical Engineering; Bladder; Candida; Candida albicans; Catheterization; Catheters; Cessation of life; Chronic; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Data; Deposition; Development; Devices; Disease; Disease Progression; Edema; Elements; Enterococcus; Enterococcus faecalis; Environment; Escherichia coli; Exhibits; Fibrinogen; Frequencies; Functional disorder; Goals; Health; Health care facility; Healthcare; Histologic; Host Defense; Hour; Human; Immobilization; Immune response; Immune system; Immunologics; Implant; In Vitro; Infection; Inflammation; Inflammatory; 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; Persons; Plants; Positioning Attribute; Predisposition; Procedures; Process; Proteins; Proteomics; Proteus mirabilis; Pseudomonas aeruginosa; Publishing; Quality of life; Recommendation; 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; antimicrobial drug; biomaterial interface; catheter associated UTI; cytokine; design; drug resistant pathogen; epithelial wound; experimental study; healing; healthcare-associated infections; immune cell infiltrate; improved; in vitro testing; in vivo; insight; methicillin resistant Staphylococcus aureus; microbial; microbial colonization; microbial host; mouse model; novel; pathogen; pathogenic bacteria; 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：现代医疗保健已采用医疗设备来帮助和改善生活质量 患有慢性疾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 它们的目的是使患者容易受到感染。导尿管是使用最广泛的导尿管之一 医疗设备，目前，导管相关尿路感染 (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 由于抗生素耐药病原体的增加，CAUTI 的控制变得越来越具有挑战性。关键的是， CAUTI 与单纯性尿路感染 (UTI) 有很大不同，表现出独特的临床和症状 病理表现以及致病微生物。例如，在不复杂的尿路感染中，大肠杆菌账户 超过 95% 的病原体，而在 CAUTI 中，导尿术可允许病原体，例如 肠球菌属、金黄色葡萄球菌、念珠菌属、奇异变形杆菌、铜绿假单胞菌和 鲍曼不动杆菌定植于膀胱，否则这种情况不会发生。鉴于 由于人口老龄化和医疗进步，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，就必须了解 CAUTI 的病理生理学。 最近的研究发现，导尿会引起膀胱炎症，并机械地破坏膀胱的正常功能。 宿主防御，损害宿主的微生物定植。在小鼠和人类中的进一步发现 表明纤维蛋白原（Fg）被释放并积聚在膀胱中以治愈受损组织。 Fg也是 沉积在导管上，覆盖导管并形成 CAUTI 相关病原体定植的平台。 研究发现，Fg 水平可调节感染结果，在缺乏 Fg 的情况下，粪肠球菌无法调节感染的结果。 坚持导管并定植于膀胱。另一方面，高 Fg 水平会增强肠球菌膀胱 和导管定植。这表明导尿管上的蛋白质沉积是微生物产生的关键因素。 感染。该提案测试了以下假设：通过控制表面上的蛋白质沉积量 使用新型液体表面涂层，我们将能够控制尿路病原体生物膜的速率和范围 形成、尿路定植、全身传播以及炎症反应。通过 将材料修饰、蛋白质组学、组织学和免疫学方法与小鼠结合起​​来 CAUTI 模型，我们将：1）开发控制蛋白质沉积的液体注入导管； 2）评估他们的 有助于减少体外蛋白质沉积和生物膜形成； 3) 表征体内蛋白质如何 沉积调节影响生物膜的形成、感染的结果和炎症。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 的建立和进展，为替代治疗的发展提供了重要见解 不会导致微生物耐药性。