HOST CELL INTERACTIONS BY PATHOGENIC BORRELIAE

致病性疏螺旋体与宿主细胞的相互作用

• 批准号: 6692619
• 负责人: JOHN M LEONG
• 金额: $ 35.1万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6692619
• 关键词: Borrelia; CD antigens; Lyme disease; bacteria infection mechanism; bacterial genetics; bacterial proteins; blood circulation; erythrocytes; flow cytometry; histopathology; host organism interaction; human tissue; integrins; laboratory mouse; leukocyte adhesion molecules; mucopolysaccharides; platelet activation; platelet aggregation; polymerase chain reaction; protein binding; protein structure function; proteoglycan; reticuloendothelial system; tissue /cell culture; virulence

DESCRIPTION (Adapted from the Applicant's Abstract): Borrelia burgdorferi is the causative agent of Lyme disease, and B. hermsii and B. turicatae are causative agents of tick-borne relapsing fever. Pathogen-host cell interactions are thought to be critical determinants of the site and severity of infection, and Dr. Leong's group has focused on Borreliae recognition of two classes of host cell molecules: (1) glycosaminoglycans (GAGs); and (2) integrins and their associated proteins. For B. burgdorferi, they have found that differences in GAG recognition were associated with differences in host cell type-specific binding, and identified a surface protein, Bgp, that may be the major B. burgdorferi GAG receptor. This bacterium also recognizes the activation-dependent platelet integrin alphaIIbbeta3 and thereby selectively binds to activated (vs. resting) platelets. This integrin-binding activity is predicted to target the Lyme disease spirochete to the vessel wall at sites of platelet adherence, and could explain a salient feature of Lyme disease: vascular pathology of the arterial circulation. In Dr. Leong's studies of relapsing fever spirochetes, high-level GAG-binding correlated with high-level growth in the bloodstream, and a variable major protein, VspB, promoted attachment to GAGs. Additionally, in contrast to B. burgdorferi, B. hermsii bound and activated resting platelets. The platelet activation activity is apparently mediated by the integrin-associated platelet-signaling molecule CD9. Dr. Leong speculates that prior to the development of an antibody response, attachment of relapsing fever spirochetes to the vessel wall, either directly via GAGs or indirectly, via activated and adherent platelets, could diminish the clearance of bacteria from the bloodstream by the reticuloendothelial system. Continued replication by these adherent bacteria would result in high level bacterial seeding of the bloodstream. Interaction of spirochetes with platelets could also contribute to thrombocytopenia, a common manifestations of relapsing fever.

描述(改编自申请人摘要)：伯氏疏螺旋体是 莱姆病的病原体，以及赫姆斯氏杆菌和图里卡特氏杆菌 壁虱传播的复发热的致病因子。病原菌-宿主细胞相互作用 被认为是感染部位和严重程度的关键决定因素， 梁博士的团队专注于识别两类疏螺旋体 宿主细胞分子：(1)糖胺多聚糖(GAG)；(2)整合素及其 相关蛋白质。对于B.burgdorferi，他们发现在 GAG识别与宿主细胞类型特异性的差异有关 结合，并鉴定了一个表面蛋白，BGP，它可能是主要的B。 Burgdorferi Gag受体。这种细菌还能识别 活化依赖的血小板整合素αIIbbeta3，从而选择性地 与激活的(与静息的)血小板结合。这种整合素结合活性是 预测以莱姆病螺旋体为靶标的部位的血管壁 血小板黏附，并可以解释莱姆病的一个显著特征： 动脉循环的血管病理学。 在梁博士对回归热螺旋体的研究中，高水平的插嘴结合 与血液中的高水平增长相关，以及一种可变的主要 蛋白质VspB促进了对GAG的附着。此外，与B. Burgdorferi、B.hermsii结合并激活静息血小板。血小板膜 激活活性显然是由整合素相关的 血小板信号分子CD9。梁智鸿博士推测，在 复发性发热螺旋体的抗体反应、附着的形成 直接通过GAG或间接通过激活和 黏附的血小板，会减少细菌从血小板上的清除 血流通过网状内皮系统。通过以下方式继续复制 附着的细菌会导致高水平的细菌播种 血液流动。螺旋体与血小板的相互作用也可能有助于 血小板减少症，复发发烧的常见表现。