Pathogenesis of pseudorabies virus (PRV):

描述（由申请人提供）：PRV是甲疱疹病毒亚家族的成员，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。甲疱疹病毒在序列和功能上有显著的保守性，而且大多数甲疱疹病毒都倾向于感染宿主的外周神经系统和中枢神经系统。用野生型PRV毒株（PRV- becker）与无毒活疫苗PRV毒株（PRV-Bartha）进行的研究表明，在Bartha基因组中所有已知的突变中，只有三种病毒基因产物对神经毒力至关重要。这三种蛋白分别是糖蛋白E （gE）、糖蛋白I （gl）和US9 （US9）磷蛋白。我们已经建立了一种PRV发病机制的小鼠侧腹感染模型，该模型提供了多种毒力表型，以前从未有过详细的分子分析。我们已经证明，受贝克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，从而产生严重的侧翼皮肤损伤。这些动物死亡的速度和它们表现出的临床症状表明，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,这些动物显示严重CMS异常。这表明，由于动物不会产生有毒的全身炎症反应，病毒能够进入大脑并复制，从而诱发致命的脑炎。我们推测，诱导宿主免疫和神经系统对PRV反应的关键病毒蛋白是糖蛋白E、糖蛋白I和US9蛋白。

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.