Herpes simplex (HSV) egress at synapses

单纯疱疹病毒（HSV）在突触处的出口

基本信息

批准号：
10413227
负责人：
Ian B Hogue
金额：
$ 19.63万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-27 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413227
关键词：
Adopted Adult Afferent Neurons Animals Axon Back Biological Factors Biological Process Biomedical Engineering Cell Adhesion Molecules Cell Culture Techniques Cell membrane Cell surface Cells Cellular biology Clinical Dendrites Development Disease Elderly Encephalitis Exocytosis Fluorescence Microscopy Foundations Future Glass Goals Herpes Simplex Infections Herpes encephalitis Herpesviridae Herpesvirus 1 Heterodimerization High Prevalence Homo Image Immunocompromised Host In Vitro Individual Interneurons Invaded Lead Lesion Location Membrane Proteins Methods Molecular Molecular Biology Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Organelles Pattern Peripheral Peripheral Nervous System Persons Population Process Recurrence Research Specific qualifier value Spottings Surface Synapses Synaptic Cleft Technology Tissues Viral Viral Vector Virion Virus Virus Assembly druggable target imaging study in vivo innovation insight lytic replication member method development neonate neural circuit neuroinflammation neuropathology novel particle reactivation from latency synaptogenesis tool trafficking

项目摘要

Herpes Simplex Virus 1 (HSV-1), a member of the alpha herpesvirus subfamily, is among the very few viruses that naturally and productively exploit the mammalian nervous system, and, accordingly have evolved neuron- specific mechanisms to interact with highly-specialized neuronal cell biology. During the typical course of disease, alpha herpesviruses infect and establish latency in the peripheral nervous system (PNS). During lytic replication, such as following reactivation from latency, progeny virus particles spread back to peripheral tissues, causing recurrent herpetic lesions, and can also spread into the central nervous system (CNS). HSV-1 invasion of the CNS can cause severe and debilitating herpes encephalitis, or can be asymptomatic/sub- clinical. Once in the CNS, HSV-1 may trigger neuroinflammation and contribute to the development of neurodegenerative disease. To better understand the molecular and cellular mechanisms that underlie HSV-1 spread to the CNS, we propose an innovative method development/bioengineering goal: to develop methods to directly image virus particle exocytosis at or near neuronal synapses. This will involve culturing primary neurons on patterned substrates in order to induce synapse formation at defined locations and orientations. We will combine this method with our established live-cell virus exocytosis method to be able to image and study cell biological factors involved in viral exocytosis at or near synapses. Elucidating the basic cell biological processes that HSV-1 uses in neurons will increase our understanding of how and why herpesviruses spread in the nervous system, lead to the identification of druggable targets and development of better therapies for viral neuropathology, and may provide fundamental insights into the cell biology of neurons.

单纯疱疹病毒1（HSV-1）是Alpha疱疹病毒亚家族的成员，是很少有自然而有效地利用哺乳动物神经系统的病毒之一，因此，它已经发展为神经元的机制，可以与高度特异性的神经元细胞生物学相互作用。在典型的疾病过程中，α疱疹病毒感染并在周围神经系统（PNS）中建立潜伏期。在裂解复制期间，例如遵循潜伏期的重新激活，后代病毒颗粒散布回周围组织，导致复发性疱疹病变，也可以扩散到中枢神经系统（CNS）中。 HSV-1侵袭中枢神经系统会导致严重和使人衰弱的疱疹脑炎，或者可能是无症状/临床的。一旦进入中枢神经系统，HSV-1可能会触发神经炎症并有助于神经退行性疾病的发展。为了更好地理解HSV-1基础扩展到中枢神经系统的分子和细胞机制，我们提出了一种创新的方法开发/生物工程目标：开发方法以直接对神经元突触或靠近神经元突触的病毒颗粒胞吐作用。这将涉及在图案化底物上培养主要神经元，以诱导定义的位置和方向的突触形成。我们将这种方法与已建立的活病毒胞吐作用方法相结合，以能够形象和研究参与突触或附近突触的病毒胞吐作用的细胞生物学因素。阐明HSV-1在神经元中使用的基本细胞生物学过程将增加我们对疱疹病毒在神经系统中如何以及为什么传播的理解，导致对可药物靶标的鉴定以及对病毒神经病理学的更好疗法的发展，并可能为神经元细胞生物学提供基本的见解。