Anaplasma - B. burgdorferi /endothelium interactions

无形体 - 伯氏疏螺旋体/内皮相互作用

基本信息

批准号：
6867827
负责人：
Dennis John Grab
金额：
$ 18.75万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2004-12-05 至 2006-11-30
项目状态：
已结题

项目摘要

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）：莱姆病是由鹿蜱传播的螺旋体伯氏疏螺旋体引起的，其症状包括从皮肤感染到血液侵入心脏、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、肩胛硬蜱传播。临床研究、血清学研究和动物研究越来越多地表明，嗜吞噬细胞放线菌的共感染可能会导致莱姆病的严重程度和并发症。大多数共感染研究的重点是嗜吞噬细胞调节菌对伯氏疏螺旋体的免疫反应。然而，蜱传播的病原体之间的一个共同联系是进入血液进行传播和穿过血管壁的能力。初步研究表明，伯氏疏螺旋体与内皮细胞的结合和通过部分是由宿主基质金属蛋白酶（MMP）介导的，并且伯氏疏螺旋体和嗜吞噬细胞球菌感染的中性粒细胞与内皮细胞的共孵育增强了伯氏疏螺旋体的迁移。 A. 嗜吞噬细胞感染的中性粒细胞释放趋化因子，并在血小板选择素糖蛋白配体 (PSGL)-1 (CD162) 和 L-选择素 (CD62L) 粘附分子表达显着丧失后失去粘附活化内皮细胞的能力。虽然 MMP 抑制剂可逆转 L-选择素损失，但只有二价阳离子螯合剂才能逆转表面 PSGL-1 的脱落。数据表明 MMP 和一种新的脱落酶参与其中。因此，表明新型 PSGL-1 脱落酶或趋化因子在伯氏疏螺旋体的迁移和传播中具有协同作用。拟议研究的假设是，由嗜吞噬细胞球菌引发的功能性中性粒细胞变化（包括趋化因子或 MMP 释放）增强了伯氏疏螺旋体穿过血管屏障的天然能力。我们建议：（1）量化和定义嗜吞噬细胞A.增强伯氏疏螺旋体跨血管和脑微血管内皮细胞的迁移的动力学； (2) 确定特定的伯氏疏螺旋体轮回增强因子，例如 MMP、趋化因子或嗜吞噬细胞球菌感染细胞的其他生物活性产物。从拟议的研究中获得的结果将确定双重感染在伯氏疏螺旋体的传播中是否存在独特的非免疫作用。阐明增强作用的步骤可能有助于对莱姆病、HGE 和合并感染的毒力机制进行更深入的基础和临床研究。