Receptors Involved in Microglial Responses to S. aureus

参与小胶质细胞对金黄色葡萄球菌反应的受体

基本信息

批准号：
6897919
负责人：
Tammy L Kielian
金额：
$ 29.2万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-06-13 至 2007-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Microglia are one of the resident mononuclear phagocyte populations within the central nervous system (CNS). These cells share many phenotypical and functional characteristics with macrophages, indicating that microglia participate in innate immune responses in the brain. We have recently demonstrated that microglia are capable of recognizing S. aureus and respond by elaborating numerous inflammatory mediators and exhibit bactericidal activity. As such, microglia are uniquely poised to provide an initial line of defense against invading microorganisms into the CNS prior to leukocyte infiltration. However, the receptor(s) responsible for mediating microglial activation in response to S. aureus have not been identified. The pattern recognition receptors (PRRs) Toll-like receptor 2 (TLR2) and CD 14 play a pivotal role in macrophage activation in response to the gram-positive cell wall products peptidoglycan (PGN) and lipoteichoic acid (LTA). We have recently revealed that microglia express both of these PRRs which may be responsible for mediating cell activation in response to S. aureus. With the goal of defining the role(s) of TLR2 and CD14 in microglial responses to pyrogenic bacteria in the CNS, the following specific aims are proposed: I) To characterize the response of microglia to intact S. aureus organisms, PGN, LTA, and secreted virulence factors in terms of inflammatory mediator production; II) To examine the expression and regulation of TLR2 and CD14 on microglia; III) To delineate the functional significance of TLR2 and CD14 expression on microglial activation using microglia from receptor knockout mice, receptor blocking antibodies, and transient transduction of dominant negative receptor constructs; and IV) To examine the importance of microglial TLR2 and CD14 expression in the pathogenesis of S. aureus-induced brain abscesses using receptor knockout mice and radiation bone marrow chimeras. Although we are examining microglial activation in response to S. aureus, it is likely that our findings will extend to other gram-positive organisms by virtue of their conserved structural components. Understanding the mechanisms by which microglia recognize and respond to microbial products could have a significant impact on a broad range of bacterial infectious diseases in the CNS.

描述（由申请人提供）：小胶质细胞是其中的一种中枢神经系统（CNS）内的单核吞噬细胞群。这些细胞与以下细胞有许多共同的表型和功能特征巨噬细胞，表明小胶质细胞参与先天免疫反应在大脑中。我们最近证明小胶质细胞能够识别金黄色葡萄球菌并通过阐述大量炎症反应来做出反应介质并表现出杀菌活性。因此，小胶质细胞具有独特的准备提供抵御微生物入侵的第一道防线在白细胞浸润之前进入中枢神经系统。然而，受体负责介导小胶质细胞激活以响应金黄色葡萄球菌未被识别。模式识别受体 (PRR) 类似 Toll 受体 2 (TLR2) 和 CD 14 在巨噬细胞激活中发挥关键作用对革兰氏阳性细胞壁产物肽聚糖（PGN）的反应和脂磷壁酸（LTA）。我们最近发现小胶质细胞表达这两种这些 PRR 可能负责介导细胞激活对金黄色葡萄球菌的反应。目标是定义 TLR2 和 CD14 的作用在小胶质细胞对中枢神经系统热原细菌的反应中，以下提出了具体目标： I) 表征小胶质细胞对完整的金黄色葡萄球菌生物体、PGN、LTA 和分泌的毒力因子炎症介质的产生； II) 检查表达式和 TLR2 和 CD14 对小胶质细胞的调节； III) 划分功能 TLR2和CD14表达对小胶质细胞激活的意义来自受体敲除小鼠的小胶质细胞、受体阻断抗体，以及显性失活受体结构的瞬时转导； IV) 到检查小胶质细胞 TLR2 和 CD14 表达在使用受体敲除小鼠研究金黄色葡萄球菌引起的脑脓肿的发病机制和放射骨髓嵌合体。虽然我们正在研究小胶质细胞针对金黄色葡萄球菌的激活，我们的发现很可能会扩展凭借其保守的结构，与其他革兰氏阳性生物体成分。了解小胶质细胞识别和识别的机制对微生物产品的反应可能会对广泛的范围产生重大影响中枢神经系统细菌感染性疾病。