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Biophysics of the morphology and motility of Borrelia burgdorferi in diverse envi

不同环境下伯氏疏螺旋体形态和运动的生物物理学

基本信息

批准号：
8548356
负责人：
CHARLES W WOLGEMUTH
金额：
$ 27.91万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8548356
关键词：
Address Adhesions Affect Antibiotics Arthropod Vectors Asses Automobile Driving Back Bacteria Basal lamina Basement membrane Behavior Binding Biological Assay Biological Models Biophysics Black-legged Tick Blood Blood Vessels Borrelia Borrelia burgdorferi Cell Shape Cell Wall Cells Cellular Morphology Collagen Complex Coupling Dose Endothelium Environment Epithelial Cells Extracellular Matrix Extracellular Matrix Proteins Fibronectins Filament Flagella Fluorescence Microscopy Funding Gel Gelatin Goals Grant Heart Hemolymph Homologous Gene Image Immigration In Vitro Infection Invaded Joints Knock-out Lead Leptospiraceae Liquid substance Lyme Disease Mammals Measurement Measures Membrane Methods Methylcellulose Microscopic Microscopy Microspheres Midgut Modeling Molecular Conformation Morphology Mus Mutation Nervous system structure Order Spirochaetales Organ Organism Pathogenesis Penetration Penicillins Peptidoglycan Physics Point Mutation Polymers Process Proteins Relative (related person)Research Role Rotation Salivary Glands Salivary duct structure Shapes Skin Solutions Speed Stretching Surface Swimming Testing Ticks Tight Junctions Time Tissues Translations United States United States National Institutes of Health Vancomycin Vascular Endothelium Work cell behavior cell motility crosslink enzootic genetic manipulation mathematical model monolayer mutant novel therapeutics optical traps pathogen periplasm physical process public health relevance research study response transmission process

项目摘要

DESCRIPTION (provided by applicant): which is caused by the spirochete Borrelia burgdorferi, is the most common tick-transmitted illness in the United States. If untreated, Lyme disease can lead to a wide array of complications typically involving the heart, joints, or nervous system. It is widely believed that the motility of B. burgdorferi is essential for the pathogenesis of Lyme disease. B. burgdorferi swims by rotating helical filaments (flagella) that reside in the periplasmic space (the space between the outer membrane and the cell wall material). The rotation of these periplasmic flagella against the cell wall leads to deformations of the cell cylinder, and these deformations exert force against the external environment. The bacterium transitions between the arthropod vector (Ixodid ticks) and mammalian host. This enzootic cycle requires the bacterium to interact with extremely different environments. For example, spirochetes must be able to colonize the tick midgut, and then migrate out of the midgut into the hemocoel. Once in the hemocoel, the bacterium must navigate towards the salivary glands, attach to the acinar surface, penetrate the basal lamina, and enter the salivary ducts. B. burgdorferi is then inoculated into the skin of its mammalian host where it must translocate through the extracellular matrix in order to access small vessels which provide portals for dissemination through the blood. To invade joints and other host tissue, the cells must adhere to the endothelium of blood vessels in target organs and penetrate through them. The unique motility and morphology of B. burgdorferi are presumed to drive many of these processes and are, therefore, considered to be major factors in the pathogenesis of Lyme disease. The principal hypothesis of this proposal is that the internal mechanism driving the motility of B. burgdorferi (i.e., flagellar rotation) is largely unchanged when the spirochete moves between the tick and the mammalian host, but its strategy for motility is substantially different due to differences in the interactions with the different host tissues. This reasoning suggests that the shape; physical parameters, such as the stiffness of the flagella and cell cylinder; and the internal mechanism driving motility have evolved to allow for directed migration in these diverse environments. Therefore, this research will first experimentally test the predictions of a mathematical model developed by the PI that describes the shape and motility of B. burgdorferi using antibiotic-treated cells and genetic manipulations to alter the stiffnesses of the cell wall and flagella. Next, the motility of B. burgdorferi will be examined in gelatin matrices, in order to quantify motility through a controllable model system that mimics the ECM. Finally, modeling and time-lapse fluorescence microscopy will be used to determine the mechanisms of motility in epithelial cell layers, and in the tick and mouse. These aims are directed toward moving the current understanding of motility in non-physiological liquid and/or methycellulose solutions to biologically realistic environments in which spirochetes adhere to cells or ECM in order to complete their enzootic cycle and accomplish their parasitic strategy. PUBLIC HEALTH RELEVANCE: The research described in this proposal will determine the biophysical mechanisms that are involved in the transmission to and invasion of the host that occurs in Lyme disease. Specifically, a quantitative model of the pathogen-host interactions during the progression of Lyme disease will be developed and experimentally tested, which will provide a detailed understanding of the infection process and may lead to novel therapeutic methods.

描述（由申请人提供）：由伯氏疏螺旋体引起，是美国最常见的蜱传疾病。如果不及时治疗，莱姆病会导致一系列并发症，通常涉及心脏、关节或神经系统。人们普遍认为，伯氏疏螺旋体的运动对莱姆病的发病至关重要。伯氏疏螺旋体通过旋转位于质周间隙（外膜和细胞壁物质之间的空间）的螺旋细丝（鞭毛）游泳。这些质周鞭毛对细胞壁的旋转导致细胞体变形，这些变形对外部环境施加力。细菌在节肢动物媒介（蜱虫）和哺乳动物宿主之间转换。这种地方性动物循环需要细菌与极端不同的环境相互作用。例如，螺旋体必须能够在蜱虫的中肠定植，然后从中肠迁移到血液中。一旦进入血腔，细菌必须向唾液腺移动，附着在腺泡表面，穿透基底层，进入唾液腺管。然后将伯氏疏螺旋体接种到其哺乳动物宿主的皮肤中，在那里它必须通过细胞外基质转运，以便进入为血液传播提供入口的小血管。为了侵入关节和其他宿主组织，细胞必须附着在目标器官的血管内皮上并穿透它们。据推测，伯氏疏螺旋体独特的运动和形态驱动了许多这些过程，因此被认为是莱姆病发病机制的主要因素。本研究的主要假设是，当螺旋体在蜱虫和哺乳动物宿主之间移动时，驱动伯氏疏螺旋体运动的内部机制（即鞭毛旋转）在很大程度上是不变的，但由于与不同宿主组织的相互作用不同，其运动策略有很大不同。这种推理表明，形状；物理参数，如鞭毛和胞柱的刚度；驱动迁徙的内部机制已经进化到可以在这些不同的环境中进行定向迁移。因此，这项研究将首先通过实验测试PI开发的数学模型的预测，该模型描述了伯氏疏螺旋体的形状和运动，使用抗生素处理的细胞和基因操作来改变细胞壁和鞭毛的刚度。接下来，将在明胶基质中检查伯氏疏螺旋体的运动性，以便通过模拟ECM的可控模型系统量化运动性。最后，建模和延时荧光显微镜将用于确定上皮细胞层和蜱虫和小鼠的运动机制。这些目标旨在将目前对非生理性液体和/或甲基纤维素溶液中的运动性的理解转移到生物现实环境中，在这些环境中，螺旋体粘附在细胞或ECM上，以完成它们的地方病循环并完成它们的寄生策略。