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.

项目摘要/摘要 植入的医疗设备挽救了生命并改善了许多人的生活质量。但是这样 植入物仍然容易受到微生物在汇总或附近的微生物感染的影响 生物膜中的设备。超过三十年的抗菌涂料和抗生素疗法的工作 未能为生物膜感染产生强大的解决方案，这表明研究人员已经是 缺少这个难题的必不可少的一部分。我们认为预防植入物相关的关键是 感染是最早对先天免疫的更好理解和编排。在 特别是，假设中性粒细胞缓慢募集到稀疏污染的生物材料 给一些细菌成长为聚集体的时间，并保护这些骨料免于杀死 通过中性粒细胞并持续存在。在三个特定目标中，该项目将量化以下现象： 目标1。中性粒细胞募集时间到被细菌污染的生物材料表面。目标2。增长 在嗜中性粒细胞发现之前，在非生物表面附着的细菌的动力学。目标3。细菌和 中性粒细胞发现后中性粒细胞命运。这些测量将由跨学科进行 团队合并定量生化工程，分子微生物学，免疫学，免疫学， 骨科手术，生物材料以及数学和统计。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中。四个互补实验 将使用模型：1）细菌 - 人类中性粒细胞相互作用的体外视频显微镜 稀疏接种的非生物表面； 2）中性粒细胞和细菌动力学的全动物成像 皮下植入； 3）静脉内成像，单细胞分辨率的中性粒细胞分辨率 皮下植入物上的细菌动力学，以及4）常规的皮下植入物模型 用于细胞因子/基因分析，存在的免疫细胞类型的分类以及其他显微镜。 该项目将生成独特的数据集，以强调定量的，概率的表征 植入后的最初几个小时，宿主病原体相互作用，可能是 防止生物膜感染建立。这项工作将为新策略打开新的策略 通过增加中性粒细胞或加速来防止植入的医疗设备上的感染 他们将其交付给受污染的植入物具有多个潜在优势：短期干预， 广泛的适用性和抗生素耐药性问题的消除。