Biomechanics of Blood Stream Infections

描述（由申请方提供）：血管内器械相关血流感染是美国菌血症的主要原因，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抵抗宿主先天防御和抗生素的渗透。受感染的器械会喷出介质、细菌以及细菌和宿主基质的羽流，这些介质、细菌和宿主基质可能以每秒近半米的速度离开导管，并停留在肺中的微血管碎片场中或进入动脉循环。这些碎片的命运--滞留在毛细血管床中或持续存在于血液中--肯定与宿主的命运有关，并且可能由这些碎片在其寿命期间变形和断裂的趋势决定。这项工作的首要目标是机械表型这种材料，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器械感染及其并发症。这项工作是非常多学科的，并借鉴了微观流变学，应用数学和建立菌血症动物模型的专业知识。一个主要目标是通过与工程师，数学家和免疫学家合作，开发新的实验和计算工具，用于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，并使用先进的图像处理和统计模型来评估碎片内的异质性。接下来，我们将使用根据胶体化学模型改编的数学技术，从总体水平上考虑碎片。最后，我们将采用血流感染的动物模型来验证根据目标1和2的结果所做的预测，并测试通过促进细菌聚集来促进细菌清除的新方法。配备了机械表征细菌软物质在微观尺度以前不可能的，我们希望回答以下问题：当遇到毛细管，生物膜衍生的聚集体变形足以逃脱过滤？当碎片在血液中流动时，碎片会破裂成组成细菌还是以多细胞聚集体的形式存在？最后，细菌聚集体的基本机械性质如何影响急性危及生命的血流感染中的宿主-病原体相互作用，以及如何在治疗上利用这些性质？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。额外的好处包括内在价值，在生物物理学，而不是免疫学，背景下，并在开发测量和计算策略，扩展到许多其他领域感兴趣的微观粘弹性材料的行为的血流感染的问题。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细菌小聚集体的生物物理特性。血液感染是常见的，并且经常是致命的，特别是在免疫功能低下的患者中，例如那些正在接受癌症治疗的患者。我们正在进行研究，以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流感染患者的新策略。

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.