"Pathogenesis of pseudorabies virus (PRV):

“伪狂犬病病毒（PRV）的发病机制：

• 批准号: 6872670
• 负责人: ASHLEY E REYNOLDS
• 金额: $ 12.8万
• 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/6872670
• 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.

性状（由申请方提供）：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（BHV-1）一起属于α疱疹病毒亚科沿着成员。在α疱疹病毒中存在显著的序列和功能保守性，并且这些病毒中的大多数表现出对它们的宿主物种的外周神经系统（PNS）和中枢神经系统（CNS）的感染的偏好。用野生型PRV毒株（PRV-Becker）与无毒力活疫苗PRV毒株（PRV-Bartha）进行的研究表明，在Bartha基因组的所有已知突变中，只有三种病毒基因产物对神经毒力至关重要。这三种蛋白质是糖蛋白E（gE）、糖蛋白I（gl）和US 9（US 9）磷蛋白。我们已经开发了一个小鼠侧腹感染模型的PRV发病机制，提供了各种毒力表型以前从未提供详细的分子分析。我们已经证明，感染Becker的小鼠迅速死亡，并在接种部位对病毒诱导的刺激作出反应而自残，从而产生严重的侧腹皮肤损伤。这些动物死亡的速度和它们表现出的临床体征表明，它们屈服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感染动物的两倍多，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，由于动物没有产生毒性全身炎症反应，因此病毒能够进入大脑并复制以诱导致命的脑炎。我们推测，诱导宿主对PRV的免疫和神经系统应答所必需的关键病毒蛋白是糖蛋白E、糖蛋白I和US 9蛋白。