Biomechanics of Blood Stream Infections

描述（由申请人提供）：在美国，与血管内器械相关的血流感染是导致菌血症的主要原因，是患病和受伤患者中常见的危及生命的并发症。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可以抵抗宿主先天防御和抗生素的渗透。受感染的装置喷射出一股介质、细菌、细菌和宿主基质，它们可能以每秒近半米的速度离开导管，要么停留在肺部的微血管碎片区，要么进入动脉循环。这些碎片的命运——被困在毛细血管床上或留在血液中——肯定与宿主的命运有关，并且可能由这些碎片在其生命周期中变形和断裂的趋势决定。这项工作的首要目标是对这种材料进行机械表型分析，并通过实验将这些生物体的力学与体内行为联系起来，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，并利用了微流变学、应用数学和已建立的菌血症动物模型方面的专业知识。一个主要目标是通过与工程师、数学家和免疫学家的合作，开发新的实验和计算工具来评估微观非线性粘弹性颗粒。我们的第一个目标是量化生物膜碎片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片内部的异质性。接下来，我们将使用从胶体化学模型改编的数学技术在种群水平上考虑碎片。最后，我们将采用血液感染的动物模型来验证从目标1和2的结果中做出的预测，并测试一种通过促进细菌聚集来促进细菌清除的新方法。利用以前不可能在微观尺度上对细菌软物质进行的机械表征，我们希望回答以下问题：当遇到毛细管时，生物膜衍生的聚集体能否变形到足以逃脱过滤？当这些碎片在血液中流动时，它们会分裂成细菌的组成部分，还是保持多细胞聚集体的形态？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-病原体相互作用，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力学。其他好处包括在生物物理而非免疫学背景下重新定义血流感染问题的内在价值，以及在发展测量和计算策略方面的内在价值，这些策略延伸到对微观粘弹性材料行为感兴趣的许多其他领域。该项目的目标是更好地了解在危及生命的感染期间进入血液的小群细菌的生物物理特性。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，如正在接受癌症治疗的患者。我们正在进行的研究是为了更好地了解患者和细菌如何相互作用，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.