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.

项目摘要/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 在少数进化以利用高度特异性神经元细胞生物学的病毒中。在 天然疾病的病程，α疱疹病毒感染周围神经系统（PNS）神经节， 终身潜在感染，偶尔重新激活以引起周围组织中复发性病变，或者可以 传播以感染中枢神经系统。重新激活，复制和组装后，后代病毒 颗粒可以从感染神经元的soma/dendrites中退出，也可以分类成轴突并进行长期 距离轴突运输。特别是HSV-1是病毒脑炎的主要原因，也可能有助于 神经退行性疾病的发展。 该补充建议的主要目的是确定基于微管电机 介导轴突分选的机制，特别是在PNS神经元中。在AIM 1中，我们将确定 后代病毒颗粒的细胞内转运中不同的驱动蛋白电机和微管相关蛋白 通过活细胞成像在非神经元细胞中。在AIM 2中，我们将确定这些电动机的作用和 使用微流体样腔室的轴突分选的微管相关蛋白 神经元培养系统。在此补充应用中，提出的实验是新颖的，但在 父母R01奖的范围。 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什么传播到神经系统内部和内部的理解， 导致鉴定可药物靶标并开发更好的病毒神经病理学疗法，并 可以提供对细胞生物学的基本见解，特别是神经元细胞生物学。