Maintenance of Blood-Brain Barrier Integrity as a Neurotropic Virus Immunizaiton

作为嗜神经病毒免疫维持血脑屏障完整性

基本信息

批准号：
7480313
负责人：
Douglas Craig Hooper
金额：
$ 19.01万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7480313
关键词：
3-nitrotyrosine Adherence Amino Acids Animals Area Astrocytes Attenuated Blood - brain barrier anatomy Blood Circulation CD4 Positive T Lymphocytes Categories Cell Adhesion Molecules Cell Communication Cells Chiroptera Defect Endothelial Cells Failure Flow Cytometry Genes Human Immune Immune response Immunity Immunohistochemistry In Vitro Infection Interferon Type II Interferons Laboratories Localized MHC Class II Genes Maintenance Mediating Membrane Glycoproteins Modeling Modification Molecular Mus Neuraxis Other Therapy Peripheral Permeability Peroxonitrite Process Production Prohibit Rabies virus Reverse Transcriptase Polymerase Chain Reaction Silver Surface Techniques Testing Therapeutic Tissues Variant Vascular Endothelial Cell Viral Virus Virus Diseases base congenic design human SILV protein insight mRNA Expression neurotoxic neurotropic neurotropic virus novel pathogen prevent receptor research study response success

项目摘要

DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) is a specialization of the neurovasculature that regulates contact between the contents of the circulation and CNS tissues. The integrity of the BBB must be transiently compromised for immune effectors to enter the CNS tissues to clear a neurotropic virus infection. During the clearance of a laboratory attenuated rabies virus strain, CVS-F3, from the CNS, increased BBB permeability is CD4 T cell dependent and associated with the production of IFN-? and nitrotyrosine formation in corresponding areas of the neurovasculature. We have recently established that infection with wildlife rabies viruses (RV), such as the highly pathogenic silver-haired bat-associated rabies virus (SHBRV), is lethal despite the induction of innate and adaptive immunity because the maintenance of BBB integrity prevents immune effectors from reaching the CNS tissues. This is the first description of a process that allows a neurotropic virus to escape immune clearance by interfering with the mechanism responsible for enhanced BBB permeability. Understanding how this occurs is important with respect to the design of therapeutic strategies for the emerging SHBRV infection of humans as well as, likely, for other neurotropic infections. The objective of this project is to identify the precise steps in the anti-viral, immune-mediated induction of enhanced BBB permeability that occurs in CVS-F3 infected animals but are absent in SHBRV-infected animals. Immunohistochemical, cellular and molecular techniques will be used to characterize the activity of CD4 T cells, vascular endothelial cells, and BBB-associated astrocytes as well as the changes that occur at the BBB during infection.

描述（由申请人提供）：血脑屏障（BBB）是神经腔的专业化，可调节循环内容和中枢神经系统组织之间的接触。必须将BBB的完整性暂时妥协，以使免疫效应子进入中枢神经系统组织清除神经性病毒感染。在清除实验室减弱的狂犬病病毒菌株中，CVS-F3从中枢神经系统中提高的BBB渗透性增加是CD4 T细胞的依赖性，并且与IFN-的产生有关？在神经血管内的相应区域中的硝基酪氨酸形成。我们最近确定，野生动植物狂犬病病毒（RV）的感染，例如高度致病的银发蝙蝠相关狂犬病病毒（SHBRV），尽管诱导了先天和适应性免疫，因为维持BBB完整性会阻止免疫效应者接触到CNS组织。这是对过程的第一个描述，该过程允许神经机病毒通过干扰负责增强BBB渗透性的机制来避免免疫清除率。了解这种情况的发生方式对于针对人类的新兴SHBRV感染的治疗策略以及其他神经性感染的可能性很重要。该项目的目的是确定在CVS-F3感染动物中发生的抗病毒，免疫介导的增强BBB渗透性的诱导的精确步骤，但在SHBRV感染的动物中不存在。免疫组织化学，细胞和分子技术将用于表征CD4 T细胞，血管内皮细胞和与BBB相关的星形胶质细胞的活性以及感染期间BBB发生的变化。