Anaplasma - B. burgorferi/endothelijm interactions

无形体 - 伯氏疏螺旋体/内皮细胞相互作用

• 批准号: 6987913
• 负责人: Dennis John Grab
• 金额: $ 18.43万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-05 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6987913
• 关键词: Borrelia; Lyme disease; Rickettsiales; Spirochaetales; arthropod borne communicable disease; bacteria infection mechanism; bioassay; brain; cell line; chemokine; communicable disease transmission; comorbidity; cytokine; fluorescent dye /probe; host organism interaction; human subject; membrane permeability; metalloendopeptidases; neutrophil; scintillation counter; transmission electron microscopy; vascular endothelium; western blottings

DESCRIPTION (provided by applicant): The manifestations of Lyme disease, caused by the deer tick-transmitted spirochete, Borrelia burgdorferi, range from skin infection to bloodstream invasion into the heart, joints, and nervous system. Human granulocytic anaplasmosis (HGA) is caused by Anaplasma phagocytophilum, a rickettsia of neutrophils that is also transmitted by the deer tick, Ixodes scapularis. Clinical investigations, serologic studies, and animal studies increasingly suggest that coinfection with A. phagocytophilum may contribute to severity and complications of Lyme disease. Most coinfection studies focus on A. phagocytophilum-modulated immune response to B. burgdorferi. However, a common link between tick-transmitted pathogens is access to blood for dissemination and the ability to pass through blood vessel walls. Preliminary studies show that B. burgdorferi binding and passage through endothelial cells is in part mediated by host matrix metalloproteases (MMPs), and that coincubations of B. burgdorferi and A. phagocytophilum-infected neutrophils with endothelial cells enhance transmigration of B. burgdorferi. A. phagocytophilum-infected neutrophils release chemokines and lose the ability to adhere to activated endothelial cells after significant loss of platelet selectin glycoprotein ligand (PSGL)-1 (CD162) and L-selectin (CD62L) adhesion molecule expression. While MMP inhibitors reverse L-selectin loss, only divalent cation chelators reverse shedding of surface PSGL-1. The data suggest the involvement of MMPs and a novel sheddase. Thus, a synergistic role for the novel PSGL-1 sheddase or chemokines is suggested in B. burgdorferi transmigration and dissemination. The hypothesis of the proposed research is that functional neutrophil changes triggered by A. phagocytophilum, including chemokine or MMP release, enhance the native ability of B. burgdorferi to transit across vascular barriers. We propose to: (1) quantify and define the kinetics of A. phagocytophilum enhanced B. burgdorferi transmigration across vascular and brain microvascular endothelial cells; and (2) define the specific B. burgdorferi transmigration enhancing factors such as MMPs, chemokines, or other biologically active products of A. phagocytophilum-infected cells. The results obtained from the proposed study will establish whether a distinctive non-immunologic role for coinfection exists in the dissemination of B. burgdorferi. The elucidation of the steps that explain the enhancement may allow for more intensive basic and clinical investigation into mechanisms of virulence for Lyme disease, HGE, and coinfections.

描述（由申请人提供）：莱姆病的表现，由鹿蜱传播的螺旋体，伯氏疏螺旋体引起，范围从皮肤感染到血流侵入心脏，关节和神经系统。人类粒细胞无形体病（HGA）是由嗜吞噬细胞无形体引起的，这是一种中性粒细胞立克次体，也由鹿蜱，肩突硬蜱传播。临床研究、血清学研究和动物实验越来越多地表明，与A.嗜吞噬细胞菌可能导致莱姆病的严重程度和并发症。大多数合并感染研究集中在A.嗜吞噬细胞调节的对B的免疫应答。burgdorferi。然而，蜱传播的病原体之间的一个共同联系是进入血液传播和通过血管壁的能力。初步研究表明，B.伯氏菌结合和通过内皮细胞部分由宿主基质金属蛋白酶（MMP）介导，且B的共孵育。burgdorferi和A.具有内皮细胞的嗜吞噬细胞感染的中性粒细胞增强B的迁移。burgdorferi。 A.在血小板选择素糖蛋白配体（PSGL）-1（CD 162）和L-选择素（CD 62 L）粘附分子表达显著丧失后，嗜吞噬细胞菌感染的中性粒细胞释放趋化因子并丧失粘附至活化内皮细胞的能力。虽然MMP抑制剂逆转L-选择素损失，但只有二价阳离子螯合剂逆转表面PSGL-1的脱落。这些数据表明MMPs和一种新的脱落酶的参与。因此，在B中提示了新的PSGL-1脱落酶或趋化因子的协同作用。burgdorferi的迁移和传播。本研究假设A.嗜吞噬细胞因子，包括趋化因子或MMP释放，增强B的天然能力。通过血管屏障。我们提出：（1）定量和定义A.嗜吞噬细胞菌增强B。通过血管和脑微血管内皮细胞的burgdorferi易位;和（2）定义特异性B。伯氏螺旋体迁移增强因子，如MMPs、趋化因子或其它伯氏螺旋体的生物活性产物。嗜吞噬细胞感染的细胞。本研究的结果将确定在B传播中是否存在混合感染的独特的非免疫学作用。burgdorferi。阐明解释增强的步骤可能允许对莱姆病，HGE和合并感染的毒力机制进行更深入的基础和临床研究。