Biomechanics of Blood Stream Infections

描述(由申请人提供)：血管内设备相关的血流感染是美国菌血症的主要原因，是病人和受伤患者中常见的威胁生命的并发症。表皮葡萄球菌和肺炎克雷伯菌是血管内导管感染的常见原因，部分原因是它们产生的生物膜能抵抗宿主固有防御系统和抗生素的渗透。受感染的设备排出一股介质、细菌、细菌和宿主基质的羽流，这些物质可能以每秒近半米的速度离开导管，然后要么停在肺部的微血管碎片区域，要么进入动脉循环。这些碎片的命运--被困在毛细血管床中或留在血液中--肯定与宿主的命运有关，并可能由这些碎片在其生命周期内变形和断裂的趋势决定。这项工作的首要目标是从机械上对这种材料进行表型，并在实验上将这些生物的机制与体内的行为联系起来，以便更好地了解临床设备感染及其并发症。这项工作是非常多学科的，利用了微观流变学、应用数学和已建立的菌血症动物模型方面的专业知识。一个主要的目标是开发新的实验和计算工具，通过与工程师、数学家和免疫学家的合作来评估微观非线性粘弹性粒子。我们的第一个目标是量化生物膜碎屑的线性和非线性粘弹性特性，并使用先进的图像处理和统计模型来评估碎屑内的非均质性。接下来，我们将使用改编自胶体化学模型的数学技术，在种群水平上考虑碎片。最后，我们将使用血流感染的动物模型来验证根据AIMS 1和2的结果所做的预测，并测试一种通过促进细菌聚集来促进细菌清除的新方法。配备了以前不可能在微观尺度上对细菌软物质进行机械表征的设备，我们希望回答以下问题：当遇到毛细血管时，生物膜衍生的聚集体能否变形到足以逃脱过滤？当碎片在血流中移动时，碎片会断裂成组成细菌还是以多细胞聚集体的形式存在？最后，在危及生命的急性血流感染中，细菌聚集体的基本机械特性如何影响宿主与病原体的相互作用，以及如何利用这些特性进行治疗？这项工作的临床影响将是开辟新的治疗途径，解决血管内感染的流变学和机制。其他好处包括在生物物理学而不是免疫学背景下重建血流感染问题的内在价值，以及在开发测量和计算策略方面的内在价值，这些策略扩展到对微观粘弹性材料行为感兴趣的其他领域。公共卫生相关性该项目的目标是更好地了解在威胁生命的感染期间进入血液的小细菌聚集体的生物物理性质。血液感染很常见，而且往往是致命的，特别是在免疫功能低下的患者中，比如那些正在接受癌症治疗的患者。我们的研究是为了更好地了解患者和细菌是如何相互作用的，并寻找保护和治疗严重血液感染患者的新策略。

DESCRIPTION (provided by applicant): Intravascular device-related blood stream infection is the leading cause of bacteremia in the United States and is a common and life threatening complication among ill and injured patients. Staphylococcus epidermidis and Klebsiella pneumoniae are common causes of intravascular catheter infection, in part due to their production of biofilms that resist penetration by host innate defenses and antibiotics. Infected devices eject a plume of mediators, bacteria, and bacterial and host matrix that may leave the catheter at nearly half a meter per second and either come to rest in a microvascular debris field in the lung or pass through into the arterial circulation. The fate of this debris- entrapment in a capillary bed or persistence in the blood - is surely linked to the fate of the host, and may be determined by the tendency of these fragments to deform and fracture during their lifespan. The overarching goal of this work is mechanically phenotype this material and to experimentally link these organisms' mechanics to behavior in vivo so as to better understand clinical device infections and their complications. The work is very multidisciplinary and draws on expertise in microrheology, applied mathematics, and established animal models of bacteremia. A major objective is the development of new experimental and computational tools for evaluating microscopic nonlinear viscoelastic particles through collaboration with engineers, mathematicians, and immunologists. Our first aim is to quantify linear and nonlinear viscoelastic properties of biofilm debris and to use advanced image processing and statistical models to evaluate intra- debris heterogeneity. Next, we will consider debris at a population level using mathematical techniques adapted from models of colloid chemistry. Lastly, we will employ animal models of bloodstream infection to validate predictions made from the results of aims 1 and 2 and to test a novel means of promoting bacterial clearance by promoting bacterial aggregation. Equipped with mechanical characterizations of bacterial soft matter at a microscopic scale previously not possible, we hope to answer the following questions: When encountering a capillary, can a biofilm-derived aggregate deform sufficiently to escape filtration? When traveling in the bloodstream, will debris fracture into constituent bacteria or remain as multicellular aggregates? Lastly, how do the fundamental mechanical properties of bacterial aggregates impact host-pathogen interactions in acute life- threatening bloodstream infection and how can those properties be exploited therapeutically? The clinical impact of this work will be to open new therapeutic avenues that address the rheology and mechanics of intravascular infection. Additional benefits include intrinsic value in reframing the problem of bloodstream infection in a biophysical, rather than immunological, context and in developing measurement and computational strategies that extend into a number of other fields interested in the behavior of microscopic viscoelastic material. PUBLIC HEALTH RELEVANCE The goal of this project is to better understand the biophysical properties of small aggregates of bacteria that enter the bloodstream during life threatening infections. Blood infections are common and frequently lethal, especially in immunocompromised patients such as those undergoing treatment for cancer. Our research is being carried out to better understand how patients and bacteria interact and to look for new strategies for protecting and treating patients with serious bloodstream infections.