Neuronal Spread of Herpesvirus Infection

疱疹病毒感染的神经元传播

• 批准号: 9069998
• 负责人: Lynn W. Enquist
• 金额: $ 35.44万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069998
• 关键词: Antiviral Agents; Architecture; Area; Attenuated; Axon; Biological Assay; Biology; Cells; Cellular biology; Color; Epithelial Cells; Event; Funding; Ganglia; Goals; Health; Herpesviridae; Herpesviridae Infections; Human; Image; Imaging technology; In Vitro; Individual; Infection; Intervention; Knowledge; Label; Laboratories; Left; Modeling; Modern Medicine; Molecular; Mus; Nervous system structure; Neuroglia; Neurons; Pathogenesis; Peripheral; Peripheral Nervous System; Population; Prevention therapy; Property; Proteins; Salivary Glands; Site; Sorting - Cell Movement; Staging; Technology; Time; Tissues; Total Internal Reflection Fluorescent; Tracer; Video Microscopy; Viral; Virion; Virulent; Virus; Virus Diseases; Work; base; imaging modality; in vivo; insight; light microscopy; microscopic imaging; molecular dynamics; neural circuit; particle; research study; transmission process

DESCRIPTION (provided by applicant): One of the most exciting areas in biology is the nervous system and how it works. Viral infections of the nervous system have provided exceptional insight at many levels, from pathogenesis to basic biology. The mechanism(s) by which alpha herpesvirus infections spread into, within, and out of the nervous system are understood in principle, but not in any detail despite considerable effort. This unique biology leads to efficient host-to-host transmission and establishment of these viruses in their natural host populations with minimal pathogenesis. A long-term goal of my laboratory is to determine the molecular mechanisms by which neuroinvasive alpha-herpesviruses move in and out of the mammalian nervous system. These mechanisms will provide targets for manipulation that could substantially expand our understanding of infection transmission. Work in this renewal proposal continues to build on powerful imaging technology developed in the past funding period to reveal how herpes virion components move inside neurons and from neurons to non-neuronal cells in vitro and in vivo. We seek to identify and quantify critical events and potential bottlenecks in long distance transmission of infection from the peripheral nervous system (PNS) to peripheral epithelial cells. Experiments are divided among three aims all featuring light and video microscopy: Imaging individual virion egress events using multi-color TIRF microscopy; assaying axon-cell egress and spread events with chambered neurons, three color virus technology, and fast epifluorescence imaging; and imaging in vivo/ex vivo PRV invasion of the PNS at the single cell and single particle level. The technology and knowledge obtained from these studies have broad application. They enable a better understanding of herpesvirus cell biology at the single cell and particle level, provide insight into potential bottlenecks during hot-host transmission and have implications for intervention strategies. This technology and knowledge also will provide opportunities to develop enhanced viral tracers for understanding the organization and functional architecture of the nervous system.

描述（由申请人提供）：生物学中最令人兴奋的领域之一是神经系统及其工作原理。神经系统的病毒感染在从发病机制到基础生物学的许多层面上提供了非凡的见解。 α疱疹病毒感染传播到神经系统、内部和外部的机制原则上已被了解，但尽管付出了相当大的努力，但仍不了解任何细节。这种独特的生物学特性导致这些病毒能够在宿主之间有效传播，并以最小的发病机制在其自然宿主群体中建立。我实验室的长期目标是确定神经侵袭性α-疱疹病毒进出哺乳动物神经系统的分子机制。这些机制将为操纵提供目标，从而大大扩展我们对感染传播的理解。这项更新提案的工作继续建立在过去资助期间开发的强大成像技术的基础上，以揭示疱疹病毒粒子成分如何在神经元内部移动以及在体外和体内从神经元移动到非神经元细胞。我们寻求识别和量化从周围神经系统（PNS）到外周上皮细胞的感染长距离传播的关键事件和潜在瓶颈。实验分为三个目标，均以光学和视频显微镜为特色：使用多色 TIRF 显微镜对单个病毒体排出事件进行成像；使用腔室神经元、三色病毒技术和快速落射荧光成像分析轴突细胞的出口和传播事件；以及在单细胞和单颗粒水平上对 PNS 进行体内/离体 PRV 侵袭成像。从这些研究中获得的技术和知识具有广泛的应用。它们使人们能够在单细胞和颗粒水平上更好地了解疱疹病毒细胞生物学，深入了解热宿主传播过程中的潜在瓶颈，并对干预策略产生影响。这项技术和知识还将提供开发增强型病毒示踪剂的机会，以了解神经系统的组织和功能架构。