Genetic analysis of Herpes virus neurotropism and encephalitis

描述（由申请人提供）：单纯疱疹病毒（HSV）感染可导致复发性角膜疱疹性角膜炎，以及散发性急性脑炎。即使采用抗病毒治疗，HSV脑炎后死亡率或严重神经功能缺损的发生率仍然很高。我们的长期目标是鉴定促进HSV向中枢神经系统扩散的病毒和受感染的宿主蛋白。利用一种新的小鼠视网膜神经节细胞体内模型，我们发现HSV病毒蛋白Us9对于病毒核衣壳和病毒DNA从受感染的神经元细胞体向轴突末端的长距离传播是必需的。了解病毒靶向递送的机制可以直接识别HSV和其他嗜神经病毒感染（如巨细胞病毒和VZV）的易感步骤。我们现在建议定义Us9的区域，这是有效的核衣壳分选所必需的。我们还将定义感染轴突中与Us9相关的病毒蛋白和宿主蛋白。最后，我们将使用一种新型的微尺度培养系统测试病毒和宿主运动蛋白在被感染轴突内递送核衣壳的功能。了解病毒在成熟神经元中的病理生理学是很重要的，因为HSV在神经元之间的传播机制对于开发阻止病毒脑病传播的新抗病毒药物至关重要。此外，我们对HSV传播的了解将与对抗其他病毒感染有关。公共卫生相关性：1型单纯疱疹（HSV）和2型是大多数疱疹性脑炎病例的原因。单纯疱疹病毒也是眼部疱疹性角膜炎中角膜上皮复发性瘢痕形成的病原体，这是一种常见的致盲原因。HSV可以潜伏在受感染的神经元中，并对阿昔洛韦和阿昔洛韦衍生药物的治疗产生抗药性。因此，探索病毒感染感觉神经元并进入中枢神经系统的机制是有价值的，因为它将提供对病原体潜在脆弱性的洞察，从而可以用于治疗。

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) infections are responsible for recurrent corneal herpetic keratitis, as well as sporatic acute encephalitis. Even with antiviral treatment, the incidence of mortality or severe neurological deficits after HSV encephalitis remains high. Our long-term goal is to identify the viral and infected host proteins that promote the spread of HSV into the central nervous system. Using a novel in vivo mouse retinal ganglion cell model, we have found that the HSV viral protein, Us9, is necessary for the long distance spread specifically of viral nucleocapsid and viral DNA from an infected neuron cell body toward the axon terminal. Understanding the mechanisms underlying targeted delivery of virus leads directly to the identification of vulnerable steps in HSV and other neurotropic viral infections, such as CMV and VZV. We now propose to define the regions of the Us9 that are necessary for efficient nucleocapsid sorting. We shall also define the viral proteins and host proteins that associate with Us9 in infected axons. Lastly, we shall test the function of virus and host motor proteins in the delivery of nucleocapsids within an infected axon using a novel, microscale culture system. Understanding the pathophysiology of the virus in mature neurons is important, because the mechanisms of HSV transmission between neurons is essential for development of new antiviral drugs that block viral encephalitic spread. In addition, what we learn about HSV transmission will be relevant for fighting other virus infections. PUBLIC HEALTH RELEVANCE: Herpes simplex type 1 (HSV) and type 2 are responsible for the majority of herpetic encephalitis cases. HSV is also the pathogen responsible for recurrent scarring of the corneal epithelium in ocular herpetic keratitis, a common cause of blindness. HSV can become latent in infected neurons and can become resistant to treatment with acyclovir and acyclovir-derived drugs. Thus, exploration of the mechanisms used by the virus to infect sensory neurons and travel to the central nervous system is of value in that it will provide insight into potential vulnerabilities of the pathogen that can be exploited therapeutically.