MECHANISMS OF HSV-1 TRANSPORT IN CNS NEURONS

HSV-1 在 CNS 神经元中的转运机制

• 批准号: 6394054
• 负责人: Judy Ann Garner
• 金额: $ 24.38万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394054
• 关键词: SDS polyacrylamide gel electrophoresis; cell membrane; cell nucleus; cytoskeleton; density gradient ultracentrifugation; herpes simplex virus 1; host organism interaction; intercellular connection; intracellular transport; laboratory mouse; microtubules; nervous system infection; neuronal transport; neurons; synapses; virus infection mechanism; virus protein; western blottings

Viruses of the family Herpesviridae, including herpes simplex types 1(HSV1) and 2, varicella zoster virus, cytomegalovirus, and Epstein-Barr Virus are complex enveloped viruses containing linear double-stranded DNA. As a group, they are responsible for a large number of serious human ailments. In its natural host, the adult human, the cold virus HSV1 primarily infects oral mucosal epithelium, followed by infection of sensory neurons innervating that mucosa. HSV1, as with all herpesviruses, is capable of achieving latency, and can be reactivated at a later time. Though relatively rare, HSV1 can also be the primary cause of the more serious herpes simplex encephalitis, as well as systemic disseminated infections. Demonstrating increased risk of the more serious sequelae of HSV1 infection is the portion of the population that is relatively immunosuppressed (neonates, transplant patients, or those with immune-suppressive disorders). It has been well established that ocular herpetic keratitis, HSV1 infection of the eye (approximately 300,000 cases diagnosed yearly) is, after trauma, the most common cause of corneal blindness in this country. Clearly, the multiple deleterious effects of HSV1 infection thus motivate us to attempt a better understanding of host cell responses to viral infection. The targeted intracellular transport of HSV-1 is essential for transmission of virus from an infected cell to its neighbor. The synaptic connections of the infected sensory neuron (which has axons that end in the periphery and central nervous system), and the ability of these viruses to be transferred from one neuron to its synaptically linked neighbor, provide a unique route by which virus can be presented the CNS. The mechanisms by which these neurotropic viruses accomplish that intracellular movement are thus of considerable interest not only to those investigating viral pathogenesis in the central nervous system, but also to those interested in the mechanisms of basic cellular targeting and transport of endogenous macromolecular complexes. The goal of this project is to elucidate mechanisms used by HSV-1 to accomplish targetted transport from its assembly site in the neuronal cell nucleus, through the cytoplasm to the plasma membrane. We first would like to establish definitively whether viral transport depends on the presence of the microtubule cytoskeleton and microtuble-dependent motor proteins. We would like to further investigate the biological form assumed by the virus during its targetted anterograde transport. Finally, we plan to investigate host cell macromolecules that may be recruited by the virus as well as viral proteins involved in that movement.

疱疹病毒科的病毒，包括单纯疱疹1型（HSV1）和2型、水痘带状疱疹病毒、巨细胞病毒和爱泼斯坦-巴尔病毒是含有线性双链DNA的复杂包膜病毒。作为一个群体，它们对大量严重的人类疾病负有责任。在其自然宿主成人中，感冒病毒HSV1首先感染口腔黏膜上皮，然后感染支配该粘膜的感觉神经元。与所有疱疹病毒一样，HSV1能够实现潜伏期，并且可以在稍后的时间重新激活。虽然相对罕见，但HSV1也可能是更严重的单纯疱疹脑炎以及全身播散性感染的主要原因。相对免疫抑制的人群（新生儿、移植患者或免疫抑制性疾病患者）出现1型单纯疱疹病毒感染更严重后遗症的风险增加。眼部疱疹性角膜炎，即眼部疱疹病毒1型感染（每年约有30万例确诊病例），已被证实是该国创伤后角膜失明的最常见原因。显然，HSV1感染的多重有害影响促使我们尝试更好地了解宿主细胞对病毒感染的反应。1型单纯疱疹病毒的靶向细胞内转运是病毒从感染细胞向邻近细胞传播的必要条件。受感染的感觉神经元的突触连接（其轴突末端位于外周和中枢神经系统），以及这些病毒从一个神经元转移到其突触连接的相邻神经元的能力，提供了一种独特的途径，病毒可以通过这种途径进入中枢神经系统。因此，这些嗜神经病毒完成细胞内运动的机制不仅对研究病毒在中枢神经系统中的发病机制，而且对内源性大分子复合物的基本细胞靶向和运输机制感兴趣。本项目的目的是阐明HSV-1从其在神经元细胞核的组装位点，通过细胞质到质膜完成靶向运输的机制。我们首先想确定病毒转运是否取决于微管细胞骨架和微管依赖的运动蛋白的存在。我们希望进一步研究病毒在其目标顺行运输过程中所采取的生物形式。最后，我们计划研究可能被病毒招募的宿主细胞大分子以及参与该运动的病毒蛋白。