"Pathogenesis of pseudorabies virus (PRV):

“伪狂犬病病毒（PRV）的发病机制：

• 批准号: 6985415
• 负责人: ASHLEY E REYNOLDS
• 金额: $ 13.03万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985415
• 关键词: affinity chromatography; cell adhesion molecules; enzyme linked immunosorbent assay; gene expression; genetically modified animals; glycoproteins; host organism interaction; immune response; immunoprecipitation; laboratory mouse; laboratory rat; membrane potentials; membrane proteins; mutant; nervous system infection; neuropathology; pathologic process; single cell analysis; suid alphaherpesvirus 1; virulence; virus genetics; virus infection mechanism; virus protein; virus replication; yeast two hybrid system

DESCRIPTION (provided by applicant): PRV is a member of the alphaherpesvirus subfamily along with varicella-zoster virus (VZV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), monkey B virus and bovine herpesvirus type 1 (BHV-1). There is significant conservation of sequence and function amongst the alphaherpesviruses and the majority of these viruses exhibit a predilection for infection of the peripheral nervous system (PNS) and central nervous system (CNS) of their host species. Studies performed with wild-type PRV strain (PRV-Becker) compared to an avirulent, live vaccine PRV strain (PRV-Bartha) have demonstrated that, of all the known mutations in the Bartha genome, only three viral gene products are essential for neurovirulence. These three proteins are glycoprotein E (gE), glycoprotein I (gl) and US9 (US9) phosphoprotein. We have developed a mouse flank infection model of PRV pathogenesis that provides a variety of virulence phenotypes never before available for detailed molecular analysis. We have demonstrated that Becker infected mice die rapidly and self-mutilate in response to a virally induced stimulus at the site of inoculation to produce severe flank skin lesions. The rapidity with which these animals die and the clinical signs they exhibit suggest that they succumb to an overwhelming systemic inflammatory response mediated by the innate immune system. PRV-Bartha infected animals live more than twice as long as Becker infected animals, do not self-mutilate and do not develop skin lesions. However, these animals display severe CMS abnormalities. This is suggestive that, because the animals do not mount a toxic systemic inflammatory response, the virus is able to travel to the brain and replicate to induce fatal encephalitis. We hypothesize that the key viral proteins essential for induction of the host immune and nervous system responses to PRV are glycoprotein E, glycoprotein I and US9 protein.

描述（由申请人提供）：PRV 与水痘带状疱疹病毒 (VZV)、单纯疱疹病毒 1 型和 2 型（HSV-1、HSV-2）、猴 B 病毒和牛疱疹病毒 1 型同为 α 疱疹病毒亚科的成员（BHV-1）。 α疱疹病毒之间的序列和功能具有显着的保守性，并且大多数这些病毒表现出对其宿主物种的周围神经系统（PNS）和中枢神经系统（CNS）的感染的偏好。用野生型 PRV 毒株 (PRV-Becker) 与无毒活疫苗 PRV 毒株 (PRV-Bartha) 进行比较的研究表明，在 Bartha 基因组的所有已知突变中，只有三种病毒基因产物对于神经毒力至关重要。这三种蛋白是糖蛋白E (gE)、糖蛋白I (gl)和US9 (US9)磷蛋白。我们开发了 PRV 发病机制的小鼠胁腹感染模型，该模型提供了以前从未用于详细分子分析的各种毒力表型。我们已经证明，贝克尔病毒感染的小鼠在接种部位受到病毒诱导的刺激后会迅速死亡并自残，从而产生严重的胁腹皮肤损伤。这些动物死亡的速度及其表现出的临床症状表明，它们死于先天免疫系统介导的压倒性全身炎症反应。 PRV-Bartha 感染动物的寿命是 Becker 感染动物的两倍以上，不会自残，也不会出现皮肤损伤。然而，这些动物表现出严重的 CMS 异常。这表明，由于动物不会产生有毒的全身炎症反应，因此病毒能够传播到大脑并复制以诱发致命性脑炎。我们假设诱导宿主免疫和神经系统对 PRV 反应所必需的关键病毒蛋白是糖蛋白 E、糖蛋白 I 和 US9 蛋白。