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：现代医疗保健已实施医疗设备，以帮助和改善生活质量 患有慢性和生活方式疾病的人。矛盾的是，尽管这些设备成功实现了 他们的目的使患者容易感染。尿导管是使用最广泛的 医疗设备以及目前与导管相关的尿路感染（CAUTI）是最常见的 全球与医疗保健相关感染（HAI），占所有HAI的40％。另外，治疗和 由于抗生素耐药性病原体的兴起，对CAUTI的控制变得越来越具有挑战性。批判性， CAUTI与简单的尿路感染（UTI）有很大不同，该感染表现出独特的临床和 病理表现以及因果生物。例如，在简单的UTI中，大肠杆菌帐户 对于> 95％的因果剂，而在cauti中，尿导管插入术允许病原体，例如 肠球菌，金黄色葡萄球菌，念珠菌属，proteus mirabilis，pseudomonas铜绿和 baumanii acinetobacter将膀胱定居，否则不会发生这种情况。鉴于那个 由于人口老龄化和医疗进展，导管使用率的频率预计只会增加 如果我们要开发治疗和/或预防它的方法，则必须了解Cauti的病理生理学。 最近的工作发现，尿管插入术会引起膀胱炎症，并机械破坏 宿主防御，损害了微生物定植的宿主。小鼠和人类的进一步发现 表明纤维蛋白原（FG）被释放并积聚在膀胱中以治愈受损的组织。 FG也是 沉积在导管上，将其涂覆并形成由癌症相关病原体定植的平台。 发现FG水平调节感染的结果，在没有FG的情况下，粪肠球菌无法进行。 坚持导管并定居膀胱。另一方面，高FG水平增强了肠球菌膀胱 和导管定殖。这表明对尿导管的蛋白质沉积是微生物的关键因素 感染。该提案检验了以下假设：通过控制表面上的蛋白质沉积量 使用新型的液体表面涂层，我们将能够控制尿液病的生物膜的速率和程度 形成，尿路定植和全身传播以及炎症反应。通过 材料修饰，蛋白质组学，组织学和免疫方法与小鼠的结合 Cauti模型，我们将：1）开发控制蛋白沉积的液体供应导管； 2）评估他们 在体外减少蛋白质沉积和生物膜形成方面的贡献； 3）在体内表征蛋白质 沉积调节会影响生物膜的形成，感染的结果和炎症。了解 蛋白质沉积在促进病原体 - 材料宿主相互作用中的作用将在 Cauti的建立和发展，对替代治疗的发展产生关键的见解 这不会导致微生物抗性。