"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.

描述（由申请人提供）：PRV是亚家族α的成员，以及水Vericella-Zoster病毒（VZV），单纯疱疹病毒1和2型疱疹病毒（HSV-1，HSV-2），Monkey B病毒和牛疱疹病毒型1型（BHV-1）。在α鞘内病毒之间存在序列和功能的显着保守性，这些病毒大多数表现出对周围神经系统（PNS）和中枢神经系统（CNS）的偏爱。与野生型PRV菌株（PRV-becker）进行的研究与无毒的活疫苗PRV菌株（PRV-Bartha）相比，在Bartha基因组中所有已知的突变中，只有三个病毒基因产物对于神经毒素是必不可少的。这三种蛋白是糖蛋白E（GE），糖蛋白I（GL）和US9（US9）磷蛋白。我们已经开发了一种PRV发病机理的小鼠侧面感染模型，该模型提供了从未有过详细的分子分析的多种毒力表型。我们已经证明，贝克尔感染的小鼠因接种的病毒诱导的刺激而迅速死亡，自我氧化，以产生严重的侧翼皮肤病变。这些动物死亡的速度以及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的全身性炎症反应。 PRV-BARTHA感染的动物的寿命是贝克尔感染的动物的两倍以上，不要自我溶解，也不发展皮肤病变。但是，这些动物表现出严重的CMS异常。这暗示着，由于动物没有施加有毒的系统性炎症反应，因此该病毒能够传播到大脑并复制以诱导致命的脑炎。我们假设，诱导宿主免疫和神经系统对PRV的反应至关重要的关键病毒蛋白是糖蛋白E，糖蛋白I和US9蛋白。