Molecular and cellular mechanisms of HSV-1 assembly and egress

HSV-1 组装和流出的分子和细胞机制

• 批准号: 10842129
• 负责人: Ian B Hogue
• 金额: $ 3.54万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10842129
• 关键词: Award; Axon; Axonal Transport; Biological Process; Cells; Cellular biology; Central Nervous System; Dendrites; Development; Disease; Encephalitis; Ganglia; Goals; Herpesviridae; Herpesvirus 1; Intracellular Transport; Kinesin; Lead; Lesion; Mediating; Microfluidics; Microtubule-Associated Proteins; Microtubules; Molecular; Molecular Biology; Motor; Nervous System; Neurodegenerative Disorders; Neuroglia; Neurons; Parents; Peripheral; Peripheral Nervous System; Process; Recurrence; Research; Role; Sorting; Synapses; System; Tissues; Viral; Viral Encephalitis; Virion; Virus; druggable target; experimental study; human pathogen; insight; latent infection; live cell imaging; neuronal cell body; neuropathology; novel

Project Summary/Abstract Alpha herpesviruses, including the important human pathogen Herpes Simplex Virus 1 (HSV-1), are among the very few viruses that have evolved to exploit highly-specialized neuronal cell biology. During the natural course of disease, alpha herpesviruses infect peripheral nervous system (PNS) ganglia, persist as a life-long latent infection, and occasionally reactivate to cause recurrent lesions in peripheral tissues, or can spread to infect the central nervous system. Upon reactivation, replication, and assembly, progeny virus particles can exit from the soma/dendrites of infected neurons, or can sort into axons and undergo long- distance axonal transport. HSV-1, in particular, is a leading cause of viral encephalitis, and may also contribute to the development of neurodegenerative disease. The main objective of this supplement proposal is to determine the microtubule motor-based mechanisms that mediate axonal sorting, specifically in PNS neurons. In Aim 1, we will determine the roles of different kinesin motors and microtubule-associated proteins in intracellular transport of progeny virus particles in non-neuronal cells by live-cell imaging. In Aim 2, we will determine the roles of these motors and microtubule-associated proteins in axonal sorting in primary neurons, using a microfluidics-like chambered neuronal culture system. In this supplement application, the proposed experiments are novel, but are within the scope of the parent R01 award. Elucidating the basic cell biological processes that our viruses use in both neurons and non-neuronal cells will increase our understanding of how and why herpesviruses spread to and within the nervous system, lead to the identification of druggable targets and development of better therapies for viral neuropathology, and may provide fundamental insights into cell biology, particularly of the cell biology of neurons.

项目概要/摘要 α 疱疹病毒，包括重要的人类病原体单纯疱疹病毒 1 (HSV-1)， 是极少数能够利用高度专业化的神经细胞生物学的病毒之一。期间 在疾病的自然过程中，α疱疹病毒感染周围神经系统（PNS）神经节，并持续存在 终生潜伏感染，偶尔重新激活导致周围组织复发性病变，或者可以 传播并感染中枢神经系统。经过重新激活、复制和组装，子代病毒 颗粒可以从受感染神经元的体细胞/树突中排出，或者可以分类成轴突并经历长期 距离轴突运输。特别是 HSV-1，它是病毒性脑炎的主要原因，也可能导致 神经退行性疾病的发展。 该补充提案的主要目标是确定基于微管运动的 介导轴突排序的机制，特别是在 PNS 神经元中。在目标 1 中，我们将确定以下角色： 子代病毒颗粒细胞内运输中的不同驱动蛋白马达和微管相关蛋白 通过活细胞成像在非神经元细胞中进行。在目标 2 中，我们将确定这些电机的作用和 使用类似微流体的腔室在原代神经元轴突排序中微管相关蛋白 神经元培养系统。在这个补充申请中，提出的实验是新颖的，但在范围内 母公司 R01 奖项的范围。 阐明我们的病毒在神经元和非神经元中使用的基本细胞生物学过程 细胞将增加我们对疱疹病毒如何以及为何传播到神经系统以及在神经系统内传播的理解， 导致可药物靶标的识别和病毒神经病理学更好疗法的开发，以及 可能为细胞生物学，特别是神经元的细胞生物学提供基本见解。