Host-pathogen competition in IFN mediated antiviral defense

干扰素介导的抗病毒防御中宿主与病原体的竞争

基本信息

批准号：
7791337
负责人：
Douglas Craig Hooper
金额：
$ 39.87万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7791337
关键词：
Adoptive Transfer Animals Antibodies Antigen-Presenting Cells Antiviral Agents Astrocytes Attenuated Live Virus Vaccine B-Lymphocytes Blood - brain barrier anatomy CD4 Positive T Lymphocytes Cells Chiroptera Comparative Study Defect Development Engineering Exhibits Human Immune Immune response Immunity Infection Interferons Invaded Laboratories Lymphoid Mediating Molecular Mus Nature Neurons Organ Outcome Pathology Peripheral Principal Investigator Process Production Prophylactic treatment Protocols documentation Rabies Rabies virus Recombinants Regimen Response Elements Specificity Staging T-Lymphocyte Testing Tissues Treatment Protocols Vaccines Vascular Endothelial Cell Viral Antigens Viral Encephalitis Virus Virus Diseases Virus Replication disability immune clearance interest mouse model neuropathology neurotropic virus neurovascular unit neutralizing antibody novel passive antibodies pathogen research study response

项目摘要

DESCRIPTION (provided by applicant): The blood-brain barrier (BBB), a specialization of the neurovasculature that normally protects CNS tissues against immune cell invasion, and the limited ability to replace damaged neurons represent two major obstacles in clearing a neurotropic virus from the CNS. Although the mechanisms responsible for immune clearance of neurotropic virus are poorly described, viral encephalitis often resolves without permanent disability. This is not the case for infection with wild-type rabies virus (RV) where the outcome is almost always lethal if the virus reaches the CNS. Even where the RV vaccine and pre-formed virus-neutralizing antibodies (VNA) used in post- exposure prophylaxis (PEP) are available, human rabies has re-emerged. This is primarily due to infection with RV carried by bats, which is often not recognized until the virus has reached the CNS and cannot be cleared by the current PEP regimen. The recognition that many laboratory RV strains developed as live-attenuated vaccines spread to, and replicate in the CNS tissues but are cleared by immune mechanisms without overt neuropathology has led to renewed interest in why natural RV infections are not cleared from the CNS. Comparative studies of infection of mice with different RV have revealed that the defect in the immune response to wildlife strains is in the interaction between invading immune cells and cells of the neurovascular unit (NVU), including vascular endothelial cells, astrocytes and other cells that make up the BBB. In lethal rabies BBB integrity is maintained and immune effectors capable of clearing the virus cannot enter infected CNS tissues. In this project the immune-NVU interactions responsible for the delivery of immune effectors across the BBB in response to RV infection and the immune effectors that clear RV will be characterized using a variety of molecular and immunological approaches including established adoptive transfer protocols. Then the utility of novel, reverse-engineered recombinant RV vaccines in overcoming the block on clearance of lethal wildlife RV from the CNS will be assessed. These experiments will be performed in mouse models since RV infect all mammals and mice, like humans, are end-stage hosts of the virus that exhibit many of the features of human rabies. The aim is to understand how a neurotropic virus can be cleared from the CNS with minimal pathology.

描述（由申请人提供）：血脑屏障（BBB），神经血管形系统的专业化，通常保护CNS组织免受免疫细胞的侵袭，替代受损神经元的有限能力代表了清除CNS神经性病毒的两个主要障碍。尽管导致神经性病毒免疫清除的机制描述不佳，但病毒性脑炎通常在没有永久残疾的情况下可以解决。野生型狂犬病病毒（RV）感染并非如此，如果该病毒到达中枢神经系统，结果几乎总是致命的。即使在暴露后预防（PEP）中使用的RV疫苗和预形成的病毒中和抗体（VNA）也可以重新出现。这主要是由于蝙蝠携带的RV感染，这通常是直到病毒到达中枢神经系统而无法被当前PEP方案清除的。人们认识到，许多实验室RV菌株随着现场衰减的疫苗的发展而传播并在中枢神经系统组织中复制，但通过没有明显神经病理学的免疫机制来清除，这使人们对为什么未从中枢神经系统中清除天然RV感染引起了人们的兴趣。具有不同RV的小鼠感染的比较研究表明，对野生动植物菌株的免疫反应中的缺陷在于入侵的免疫细胞与神经血管单元（NVU）的细胞之间的相互作用，包括血管内皮细胞，星形胶质细胞和其他组成BBB的细胞。在致命的狂犬病中，BBB完整性得到维持，并能够清除病毒的免疫效应子无法进入感染的中枢神经系统组织。在该项目中，响应RV感染，负责免疫效应子在整个BBB中传递的免疫相互作用以及使用各种分子和免疫学方法（包括已建立的收养转移方案）来表征清晰的RV的免疫效应子。然后，将评估新型，反向工程重组的RV疫苗的实用性，以克服CNS清除致命野生动植物RV的块。这些实验将在小鼠模型中进行，因为RV感染了所有哺乳动物和小鼠，例如人类，是表现出人类狂犬病许多特征的病毒的末期宿主。目的是了解如何从CNS中清除具有最小病理的中枢神经系统。