MECHANISMS OF HSV-1 TRANSPORT IN CNS NEURONS

疱疹病毒科病毒包括单纯疱疹病毒1型和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，它们对人类的大量严重疾病负有责任。在其自然宿主成人中，感冒病毒HSV1主要感染口腔粘膜上皮，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，并可以在稍后重新激活。虽然相对罕见，但HSV1也可能是更严重的单纯疱疹病毒性脑炎以及系统性播散性感染的主要原因。表现出HSV1感染更严重后遗症的风险增加的是相对免疫抑制的那部分人群(新生儿、移植患者或患有免疫抑制障碍的人)。众所周知，眼部单纯疱疹病毒性角膜炎(HSV1感染)(每年确诊约30万例)是我国外伤后导致角膜失明的最常见原因。显然，HSV1感染的多种有害影响促使我们试图更好地了解宿主细胞对病毒感染的反应。HSV-1的靶向胞内转运对于病毒从感染细胞传播到邻近细胞是必不可少的。受感染的感觉神经元(其轴突终止于外周和中枢神经系统)的突触连接，以及这些病毒从一个神经元转移到与其突触相连的邻居的能力，提供了一条独特的途径，病毒可以通过它呈现给中枢神经系统。因此，这些嗜神经性病毒完成细胞内运动的机制不仅对研究中枢神经系统病毒发病机制的人很感兴趣，而且对内源性大分子复合体的基本细胞靶向和运输机制也很感兴趣。本项目的目标是阐明HSV-1从其在神经元细胞核中的组装位置，通过细胞质到质膜的靶向转运机制。我们首先想确定病毒的运输是否依赖于微管细胞骨架和微管依赖的马达蛋白的存在。我们想要进一步调查病毒在其目标顺行运输过程中所呈现的生物形式。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这一运动的病毒蛋白。

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.