Mechanisms of Herpes Simplex Virus

描述(申请人提供)：尽管亲神经性人类疱疹病毒(HSV-1、HSV-2和VZV)会导致急性视网膜坏死(ARN)，这是一种相对罕见但可能致盲的疾病，人们已经熟知和描述了这种疾病的临床过程，并有大量报告记录了这种疾病在人类患者中的临床过程，但对这种疾病的发病机制知之甚少。尽管没有一个疾病的动物模型与人类的疾病模型绝对一致，但对使用疾病动物模型(如ARN的小鼠模型)进行的研究结果的明智解释可能有助于理解人类疾病的发病机制。在该模型中，单眼前房接种HSV-1后，病毒感染注射眼的前段，然后通过突触连接的神经元传播到脑，最后传播到未接种的对侧眼的视神经和视网膜，导致ARN。病毒在视网膜中的复制对于视网膜的破坏是绝对必要的；然而，使用这个模型的研究支持这样的观点，即其他因素导致并加剧了未接种眼睛的视网膜破坏。因此，在这项申请中提出的研究将继续通过体外和体内方法来揭开HSV-1感染在未接种对侧眼睛的视网膜中的发病机制。为这些研究提出了两个具体目标。第一个特定目的是验证单眼前房注射HSV-1后，肿瘤坏死因子-1和肿瘤坏死因子-1诱导的细胞凋亡在ARN发病机制中起关键作用的假说，并剖析其发生的途径。第二个具体目标将检验自噬在未接种眼睛的疾病发病机制中发挥作用的假设。在短期内，为该项目提出的研究将提供关于眼睛对HSV-1感染的反应以及这种感染带来的损害的新信息。从长远来看，来自这些研究的信息可能会导致更合适的或有针对性的治疗，以控制人类疱疹病毒家族中嗜神经性成员在眼睛和大脑中的感染。这些研究还可能提供有关视网膜对感染或其他非病毒性视网膜损伤过程做出反应的更一般机制的新信息。 与公共卫生相关：虽然引起急性视网膜坏死(ARN)的嗜神经性人类疱疹病毒(HSV-1、HSV-2和VZV)是一种相对罕见但可能致盲的疾病，但众所周知，有许多报告记录了这种疾病在人类患者中的临床过程，但对这种疾病的发病机制知之甚少。这种疾病的小鼠模型中，注射到一只眼睛前房的病毒通过神经传播到大脑，并从大脑感染未接种的眼睛的视神经和视网膜，模拟在人类患者中观察到的ARN的某些方面。这项申请中提出的研究将使用培养的视网膜和病毒感染的小鼠来破译未注射眼睛的HSV-1感染的发病机制。虽然没有一个疾病的动物模型与人类的疾病模型绝对一致，但对使用ARN小鼠模型的研究结果的明智解释可能有助于我们更多地了解人类患者疱疹病毒感染的发病机制。这些信息可能有助于开发有针对性的治疗方法，但也可能提供对视网膜对感染或其他导致视网膜损伤的非感染性过程做出反应的机制的洞察。

DESCRIPTION (provided by applicant): Although the eurotropic human herpesviruses (HSV-1, HSV-2 and VZV) that cause acute retinal necrosis (ARN), a relatively rare but potentially blinding disease, are well known and well described and there are numerous reports documenting the clinical course of this disease in human patients, comparatively little is known about the pathogenesis of this disease. Although no animal model of disease has absolute fidelity to its human counterpart, judicious interpretation of results from studies using animal models of disease, such as the mouse model of ARN, may aid in understanding of the pathogenesis of human disease. In this model, following uniocular anterior chamber (AC) inoculation of HSV-1, virus infects the anterior segment of the injected eye and then spreads via synaptically connected neurons to the brain and finally to the optic nerve and retina of the uninoculated contralateral eye resulting in ARN. Replication of virus in the retina is absolutely required for retinal destruction; however, studies using this model support the idea that other factors contribute to and exacerbate retinal destruction in the uninoculated eye. Accordingly, the studies proposed in this application will continue to unravel the pathogenesis of HSV-1 infection in the retina of the uninoculated contralateral eye using both in vitro and in vivo approaches. Two specific aims are proposed for these studies. The first specific aim will test the hypothesis that TNF-1 and TNF-1 induced apoptosis are critical to the pathogenesis of ARN after uniocular anterior chamber injection of HSV-1 and dissect the pathways by which this occurs. The second specific aim will test the hypothesis that autophagy plays a role in the pathogenesis of disease in the uninoculated eye. In the short term, the studies proposed for this project will provide new information about how the eye responds to HSV-1 infection and the attendant damage from such infection. In the longer term, information from these studies may lead to more appropriate or to specifically targeted therapies to control infection by the neurotropic members of the human herpesvirus family in the eye and brain. These studies may also provide new information about more general mechanisms by which the retina responds to infection or to other non-viral retinal-damaging processes. PUBLIC HEALTH RELEVANCE: Although the neurotropic human herpesviruses (HSV-1, HSV-2 and VZV) that cause acute retinal necrosis (ARN), a relatively rare but potentially blinding disease, are well known and there are numerous reports documenting the clinical course of this disease in human patients, comparatively little is known about the pathogenesis of this disease. The mouse model of this disease in which virus injected into the anterior chamber of one eye travels via nerves to the brain and from the brain to infect the optic nerve and retina of the uninoculated eye mimics aspects of ARN observed in human patients. The studies proposed in this application will use cultured retinas and virus infected mice to decipher the pathogenesis of HSV-1 infection in uninjected eye. Although no animal model of disease has absolute fidelity to its human counterpart, judicious interpretation of results from studies using the mouse model of ARN may help us understand more about the pathogenesis of herpesvirus infections in human patients. This information may allow development of specifically targeted therapies but may also provide insight into mechanisms by which the retina responds to infection or to other non-infectious processes that result in retinal damage.