PATHOGENESIS OF INFECTION WITH THE LYME DISEASE SPIROCHETE, BORRELIA BURGDORFERI

人类感染伯氏疏螺旋体可导致多系统、 表现多样的慢性病。我们是在调查B。 Burgdorferi在几个层面上，以便了解 疾病发病机制。这些研究包括对基因的操纵 螺旋体，关键结构和调控元件的特征，以及 螺旋体在哺乳动物宿主中的传播和清除。 1.分子特征：伯氏杆菌的几个特征是 正在被寻址。编码主要外膜的基因之间的重组 伯氏杆菌表面蛋白(OspA、OSPB)可导致 OSP基因序列的缺失和生成。这样的重组体已经被 在许多菌株中检测到并表征了这些菌株。的分子基础 其他OSP表型正在调查中。隔离和研究 温度升高(热休克)后表达增加的基因 基因)将提供有关它们在细胞生长中的作用的信息，质粒 复制和适应压力。了解其作用机制 线性质粒复制可能产生抗生素的新靶点，在 除了揭示有机体如何操纵它们的 遗传物质。 2.基因转移：为了对伯氏杆菌进行遗传分析， 一种将基因转移到疏螺旋体的方法正在开发中。衍生品 16kb的线形质粒将被用作载体 电穿孔，允许在原生生物中保持转移的DNA 布景。 3.清除研究：允许伯氏杆菌逃避宿主的机制 在各种宿主组织中建立慢性感染的防御 仍然默默无闻。在哺乳动物自然感染期间，伯氏杆菌必须 首先从皮肤部位扩散到其他组织和器官。一个 鼠标清除模型已经被开发出来，使得有可能 定量评价静脉曲张的分布和清除 注射伯氏杆菌。有可能将不同类型的 具有不同结构特征的克隆生物的清除。

Infection of humans by Borrelia burgdorferi can result in a multisystemic, chronic disease with diverse manifestations. We are investigation B. burgdorferi at several levels in order to understand some aspects of the disease pathogenesis. These studies include genetic manipulations of the spirochete, characterization of key structural and regulatory elements, and dissemination and clearance of spirochetes in mammalian hosts. 1. Molecular Characterization: Several feature of B. burgdorferi are being addressed. Recombination between the genes encoding the major outer surface proteins (OspA, OspB) of B. burgdorferi can result in both the deletion and generation of osp gene sequences. Such recombinants have been detected and characterized in a number of strains. The molecular basis of additional Osp phenotypes is being investigated. Isolating and studying genes whose expression is increase after a temperature upshift (heat shock genes) will provide information about their roles in cell growth, plasmid replication and adaptation to stress. Understanding the mechanism of linear plasmid replication may yield a new target for antibiotics, in addition to shedding light on ways in which organisms manipulate their genetic material. 2. Gene Transfer: In order to allow genetic analysis of B. burgdorferi, a method for gene transfer into Borrelia is being developed. A derivative of the Borrelia 16 kb linear plasmid will be used as a vector for electroporation, allowing for maintenance of transferred DNA in a native setting. 3. Clearance Studies: Mechanisms that allow B. Burgdorferi to evade host defenses to establish chronic infections in a variety of host tissues remain obscure. During natural infections of mammals, B. burgdorferi must first disseminate from the cutaneous site to other tissues and organs. A mouse clearance model has been developed that makes it possible to quantitatively evaluate the distribution and clearance of intravenously injected B. burgdorferi. It may be possible to correlate patterns of clearance with different structural features of cloned organisms.