The Role of Borrelia Burgdorferi Chemotoxis in the Pathogenesis of Lyme Disease

描述(由申请人提供)： 莱姆病是美国最常见的节肢动物传播的传染病。这种疾病是由伯氏疏螺旋体引起的，这种螺旋体通过受感染的硬蜱传播给人类。莱姆病是一种多系统疾病，具有多种临床表现，包括红斑、游走性关节炎、肌肉骨骼和神经系统表现。在美国，大约60%的未经治疗的患者会患上莱姆关节炎。在被扁虱叮咬在皮肤中沉积后，螺旋体穿过细胞内基质，穿透血管内皮细胞衬里，并传播到靶组织。然而，这一侵入性过程中涉及的机制在很大程度上是未知的。虽然运动性和趋化性对许多病原菌的定植和/或致病至关重要，但这些过程在伯氏杆菌介导的致病机制中的作用尚未确定。三个目标将检验这一假说，即趋化性和移动性在伯氏杆菌诱导的致病过程中起关键作用。目的1：在伯氏杆菌感染性菌株中构建特异性趋化基因(如Chex和cheYS)的突变体。这些突变体的表型将根据运动性和趋化性进行表征。为了确保给定的表型不会归因于二次改变，突变的基因将得到补充。目的2：运动和趋化性对伯氏杆菌致病至关重要的假设将在莱姆病小鼠模型上进行验证。我们预测，在趋化性和运动性方面有缺陷的突变株的毒力将低于亲本菌株。目的3：我们将检验这一假说，即趋化/运动是伯氏杆菌在血餐后从扁虱中肠迁移到唾液腺的原因。野生型和突变型伯氏杆菌将通过将扁虱浸泡在富含螺旋体的溶液中而被引入扁虱的中肠。在老鼠吃了一顿血后， 野生型和突变型伯氏杆菌从扁虱中肠迁移到唾液腺的程度将被确定。所有研究的结果将提供莱姆病发病机制的关键信息，并可能为预防莱姆病(包括莱姆病相关性关节炎)的新方法提供基础。

DESCRIPTION (provided by applicant): Lyme disease is the most prevalent arthropod borne infection in the United States. The disease is caused by the spirochete Borrelia burgdorferi, which is transmitted to humans via infected Ixodes ticks. Lyme disease is a multiple systemic disorder with various clinical manifestations including erythema migrans, arthritis, musculoskeletal and neurological manifestations. In the United States, approximately 60% of untreated patients develop Lyme arthritis. After deposition in the skin by a tick bite, spirochetes traverse the intracellular matrix, penetrate the vascular endothelial cell lining, and are disseminated to target tissues. However, the mechanisms involved in this invasive process are largely unknown. While motility and chemotaxis are critical for many pathogenic organisms to colonize and/or cause disease, the role of these processes in B. burgdorferi-mediated pathogenesis has not been determined.Three aims will test the hypothesis that chemotaxis and motility are critical for B. burgdorferi-induced pathogenesis. Aim 1: mutants in specific chemotaxis genes (e.g., cheX and cheYS) will be constructed in an infectious B. burgdorferi strain. Phenotypes of these mutants will be characterized with respect to motility and chemotaxis. To ensure that a given phenotype is not attributed to secondary alterations, mutated genes will be complemented. Aim 2: the hypothesis that motility and chemotaxis are critical for B. burgdorferi pathogenesis will be tested using a mouse model of Lyme disease. We predict that mutants defective in chemotaxis and motility will be less virulent than the parental strain. Aim 3: we will test the hypothesis that chemotaxis/motility is responsible for B. burgdorferi migration from tick midgut to salivary glands following a blood meal. Wild type and mutant B. burgdorferi will be introduced into tick midguts by immersing ticks in spirochete-laden solutions. Following a blood meal on mice, the extent to which wild type and mutant B. burgdorferi have migrated from tick midguts to salivary glands will be determined. The results of all studies will provide critical information on the pathogenesis of Lyme disease and could provide the foundation for novel approaches to prevent Lyme disease including Lyme associated arthritis.