Pathogenesis of pseudorabies virus (PRV):

描述(申请人提供)：PRV是与水痘-带状疱疹病毒(VZV)、单纯疱疹病毒1型和2型(HSV-1、HSV-2)、猴子B病毒和牛疱疹病毒1型(BHV-1)一起属于甲型疱疹病毒亚科的成员。甲型疱疹病毒在序列和功能上有很大的保守性，大多数甲型疱疹病毒容易感染宿主的周围神经系统(PNS)和中枢神经系统(CNS)。用野生型PRV株(PRV-Becker)与无毒活疫苗株(PRV-Bartha)进行的比较研究表明，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是必需的。这三种蛋白分别是糖蛋白E(Ge)、糖蛋白I(Gl)和US9(US9)磷酸蛋白。我们已经建立了一种小鼠侧面感染PRV致病机制的模型，该模型提供了前所未有的各种毒力表型，用于详细的分子分析。我们已经证明，Becker感染的小鼠在接种部位受到病毒诱导的刺激后，会迅速死亡并自我破坏，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迹象表明，它们屈服于由先天免疫系统介导的压倒性全身炎症反应。感染PRV-Bartha的动物的寿命是Becker感染动物的两倍多，不会自我破坏，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性炎症反应，病毒能够传播到大脑并复制，从而引发致命的脑炎。我们推测，诱导宿主免疫和神经系统对PRV应答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.