Immunoregulation of herpes encephalitis by microglia

小胶质细胞对疱疹脑炎的免疫调节

基本信息

批准号：
7678996
负责人：
James R Lokensgard
金额：
$ 35.86万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7678996
关键词：
3-nitrotyrosine 8-hydroxy-2&apos -deoxyguanosine AIDS neuropathy Address Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptosis Biochemical Bioluminescence Brain Brain Injuries Cells Central Nervous System Infections DNA Data Development Disease Environment Enzymes Event HIV Infections HSV vector Herpes encephalitis Herpesviridae Herpesvirus 1 Image Immune In Vitro Infection Inflammation Mediators Innovative Therapy Interleukin-10 Knockout Mice Lipid Peroxidation Luciferases Measures Mediating Mediator of activation protein Microglia Modeling Mus NADPH Oxidase Neuraxis Neurons Nitric Oxide Oxidative Stress Oxidative Stress Induction Oxygen Patients Peroxidases Production Proteins Publishing Reactive Nitrogen Species Reactive Oxygen Species Receptor Signaling Recombinants Research Respiratory Burst Role Series Simplexvirus Site Staging TLR2 gene Testing Time Tissues Toll-Like Receptor 2 Toll-like receptors Transgenic Mice Vaccinia virus Viral Viral Encephalitis Viral Proteins Virus Virus Diseases base biological adaptation to stress brain tissue chemokine cytokine glutathione peroxidase heme oxygenase-1 human NOS2A protein immunoregulation in vivo inhibitor/antagonist insight isoprostaglandin F2alpha type-III knockout animal macrophage neuroinflammation novel strategies overexpression pathogen prevent programs promoter public health relevance research study response superoxide dismutase 1 tauroursodeoxycholic acid

项目摘要

DESCRIPTION (provided by applicant): Microglia and other brain macrophages are the principal regulators of neuroinflammation within the CNS. Herpes simplex virus (HSV)-1 is an important opportunistic pathogen in HIV-1-infected patients as well as the cause of a devastating CNS infection in normal hosts. It is well established that the brain damage seen during neuroAIDS is not caused by direct HIV infection of neurons, but rather is induced by macrophage-produced neuroinflammatory mediators. Microglial cells produce these same neuroinflammatory mediators in response to HSV, and this proposal utilizes HSV infection of mice as a small animal model to investigate the role of activated microglia during viral brain infection. The central hypothesis to be tested is that oxidative stress occurring during viral encephalitis can be modulated to prevent immune-mediated mechanisms of tissue damage. To test this hypothesis, we will (1) determine whether TLR2 mediates oxidative stress occurring during herpes encephalitis. This will be achieved by comparing virus-induced production of pro-oxidative enzymes and reactive species using cultured microglia isolated from wild-type versus TLR2 knockout mice. Additional experiments will compare oxidative stress-induced brain damage occurring during viral encephalitis following infection of these knockout animals. We will then (2) determine whether antioxidant enzymes regulate oxidative stress during viral encephalitis. These studies will examine the effect of select antioxidant enzymes on the production of reactive species and microglial cell apoptosis in response to HSV. We will go on to examine the role of these antioxidant enzymes in controlling oxidative stress-induced brain damage during viral encephalitis in vivo. Finally, we will (3) determine if virus-induced oxidative brain damage can be controlled. This will be achieved through overexpressing anti-inflammatory cytokines in the brains of iNOS-luciferase transgenic mice and assessing expression using in vivo real-time bioluminescence imaging. In the final studies, we will modulate the oxidative stress response occurring during herpes encephalitis. This will be achieved by constructing recombinant herpesviruses overexpressing vaccinia virus proteins that disrupt TLR signaling, as well as antioxidant enzymes, and assessing the resulting tissue damage in infected animals. Through studies described in this proposal, we hope to identify new approaches for treatment of herpes encephalitis and neuroAIDS, as well as other forms of viral encephalitis, which reduce the extent of immune-mediated brain damage. PUBLIC HEALTH RELEVANCE It is well established that brain damage seen during neuroAIDS is not caused by direct HIV infection of neurons, but rather is induced by microglial cell- produced neuroinflammatory mediators, such as reactive oxygen and reactive nitrogen species. Through the use of inhibitors of microglial cell activation and antioxidant enzymes, it may be possible to modulate the oxidative stress response occurring during viral encephalitis. In these experiments, we hope to identify new approaches to the treatment of herpes encephalitis and neuroAIDS, as well as other forms of viral encephalitis, which reduce the extent of immune- mediated mechanisms of brain damage.

描述（由申请人提供）：小胶质细胞和其他脑巨噬细胞是中枢神经系统内神经炎症的主要调节因子。单纯疱疹病毒 (HSV)-1 是 HIV-1 感染患者的重要机会病原体，也是正常宿主中毁灭性中枢神经系统感染的原因。众所周知，神经艾滋病期间出现的脑损伤不是由神经元直接感染艾滋病毒引起的，而是由巨噬细胞产生的神经炎症介质引起的。小胶质细胞响应 HSV 产生相同的神经炎症介质，该提案利用小鼠 HSV 感染作为小动物模型来研究激活的小胶质细胞在病毒脑感染期间的作用。要测试的中心假设是，可以调节病毒性脑炎期间发生的氧化应激，以防止免疫介导的组织损伤机制。为了检验这一假设，我们将 (1) 确定 TLR2 是否介导疱疹脑炎期间发生的氧化应激。这将通过使用从野生型和 TLR2 敲除小鼠中分离的培养小胶质细胞来比较病毒诱导的促氧化酶和活性物质的产生来实现。其他实验将比较这些基因敲除动物感染后病毒性脑炎期间发生的氧化应激引起的脑损伤。然后我们将（2）确定抗氧化酶是否调节病毒性脑炎期间的氧化应激。这些研究将检验特定抗氧化酶对 HSV 反应中反应性物质的产生和小胶质细胞凋亡的影响。我们将继续研究这些抗氧化酶在体内病毒性脑炎期间控制氧化应激诱导的脑损伤中的作用。最后，我们将（3）确定是否可以控制病毒引起的氧化性脑损伤。这将通过在 iNOS 荧光素酶转基因小鼠的大脑中过度表达抗炎细胞因子并使用体内实时生物发光成像评估表达来实现。在最终研究中，我们将调节疱疹脑炎期间发生的氧化应激反应。这将通过构建重组疱疹病毒来实现，该病毒过表达破坏 TLR 信号传导的痘苗病毒蛋白以及抗氧化酶，并评估受感染动物所造成的组织损伤。通过本提案中描述的研究，我们希望找到治疗疱疹脑炎和神经艾滋病以及其他形式的病毒性脑炎的新方法，从而减少免疫介导的脑损伤程度。公共健康相关性众所周知，神经艾滋病期间出现的脑损伤不是由神经元直接感染 HIV 引起的，而是由小胶质细胞产生的神经炎症介质（例如活性氧和活性氮）诱导的。通过使用小胶质细胞活化抑制剂和抗氧化酶，有可能调节病毒性脑炎期间发生的氧化应激反应。在这些实验中，我们希望找到治疗疱疹脑炎和神经艾滋病以及其他形式的病毒性脑炎的新方法，从而减少免疫介导的脑损伤机制的程度。