How Do a Few Attached Staphylococcus aureus Bacteria Evade Innate Immunity to Initiate Biofilm Infection on an Implanted Medical Device?

一些附着的金黄色葡萄球菌如何逃避先天免疫，在植入的医疗设备上引发生物膜感染？

• 批准号: 10387835
• 负责人: PHILIP S STEWART
• 金额: $ 51.06万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-07 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387835
• 关键词: Animal Model; Antibiotic Resistance; Antibiotic Therapy; B-Lymphocytes; Bacteria; Biochemical; Biocompatible Materials; Biological; Biological Models; Cataloging; Cells; Cytokine Gene; Data; Data Set; Dendritic Cells; Deposition; Development; Devices; Engineering; Experimental Models; Fibrin; Foundations; Gene Expression; Generations; Growth; Hour; Human; Immune; Immunology; Implant; In Vitro; Infection; Infection prevention; Inflammatory Response; Internal Breast Prosthesis; Intervention; Joint Prosthesis; Leukocytes; Literature; Mathematics; Measurement; Measures; Medical Device; Membrane; Microbial Biofilms; Microbiology; Microscopy; Modeling; Molecular; Motivation; Mus; Natural Immunity; Neutrophil Infiltration; Orthopedic Surgery; Outcome; Pacemakers; Phase; Quality of life; Reactive Oxygen Species; Research Personnel; Resolution; Speed; Staphylococcus aureus; Surface; Time; Video Microscopy; Work; antimicrobial; cell type; chronic infection; cytokine; density; imaging approach; implant associated infection; implantation; improved; in vivo; innate immune function; intravital imaging; macrophage; medical implant; microbial; microorganism; mouse model; neglect; neutrophil; pathogen; pathogenic bacteria; prevent; recruit; response; statistics; subcutaneous; whole animal imaging

PROJECT SUMMARY/ABSTRACT Implanted medical devices have saved lives and improved the quality of life for many. But such implants remain vulnerable to troublesome infection by microorganisms that aggregate on or near the device in a biofilm. More than three decades of work on antimicrobial coatings and antibiotic therapies have failed to produce robust solutions to biofilm infection, suggesting that researchers have been missing an essential piece of this puzzle. We contend that the key to preventing implant-related infection is a better understanding and orchestration of innate immunity at the earliest stage. In particular, it is hypothesized that slow recruitment of neutrophils to a sparsely contaminated biomaterial gives some bacteria time to grow into aggregates, and that these aggregates are protected from killing by neutrophils and persist. In three Specific Aims, this project will quantify the following phenomena: Aim 1. Neutrophil recruitment times to bacteria-contaminated biomaterial surfaces. Aim 2. Growth dynamics of bacteria attached to an abiotic surface prior to neutrophil discovery. Aim 3. Bacterial and neutrophil fates post neutrophil discovery. These measurements will be made by an interdisciplinary team merging expertise in quantitative biochemical engineering, molecular microbiology, immunology, orthopedic surgery, biomaterials, and mathematics and statistics. The primary model bacterium will be Staphylococcus aureus and the animal models will all be in mice. Four complementary experimental models will be used: 1) in vitro video microscopy of bacteria-human neutrophil interactions on a sparsely inoculated abiotic surface; 2) whole animal imaging of neutrophil and bacterial dynamics following subcutaneous implantation; 3) intravital imaging with single cell resolution of neutrophil- bacteria dynamics on a subcutaneous implant, and 4) a conventional subcutaneous implant model to be used for cytokine/gene profiling, cataloging of immune cell types present, and additional microscopy. This project will generate unique data sets emphasizing quantitative, probabilistic characterization of the host-pathogen interaction in the first several hours after implantation, the likely window for preventing a biofilm infection from establishing. This work will open the door to new strategies for preventing infections on implanted medical devices by boosting neutrophil numbers or speeding up their delivery to the contaminated implant with multiple potential advantages: short-term intervention, broad spectrum applicability, and obviation of antibiotic resistance concerns.

项目概要/摘要 植入医疗设备挽救了许多人的生命并提高了他们的生活质量。但这样的 植入物仍然容易受到聚集在植入物上或附近的微生物的麻烦感染。 生物膜中的装置。三十多年来在抗菌涂层和抗生素疗法方面的研究 未能针对生物膜感染提出强有力的解决方案，这表明研究人员一直在 缺少这个难题的一个重要部分。我们认为，预防植入相关的关键 感染是在最早阶段更好地理解和协调先天免疫。在 特别是，据推测，中性粒细胞缓慢地募集到污染稀疏的生物材料中 让一些细菌有时间生长成聚集体，并且这些聚集体不会被杀死 由中性粒细胞产生并持续存在。在三个具体目标中，该项目将量化以下现象： 目标 1. 中性粒细胞募集到细菌污染的生物材料表面的时间。目标 2. 增长 在发现中性粒细胞之前附着在非生物表面的细菌的动态。目标 3. 细菌和 发现中性粒细胞后中性粒细胞的命运。这些测量将由跨学科的人员进行 团队融合了定量生化工程、分子微生物学、免疫学、 骨科手术、生物材料、数学和统计学。主要模型细菌将是 金黄色葡萄球菌和动物模型都将在小鼠身上进行。四项互补实验 将使用模型：1）体外视频显微镜观察细菌与人中性粒细胞相互作用 稀疏接种的非生物表面； 2) 中性粒细胞和细菌动态的全动物成像 皮下植入后； 3) 中性粒细胞单细胞分辨率的活体成像 皮下植入物上的细菌动力学，以及 4) 传统的皮下植入物模型 可用于细胞因子/基因分析、现有免疫细胞类型的编目以及其他显微镜检查。 该项目将生成独特的数据集，强调定量、概率特征 植入后最初几个小时内宿主与病原体的相互作用，这可能是 防止生物膜感染的建立。这项工作将为新战略打开大门 通过增加中性粒细胞数量或加速来预防植入医疗设备上的感染 将它们输送到受污染的植入物具有多种潜在优势：短期干预， 广谱适用性，并消除抗生素耐药性问题。