Alpha-Herpesvirus Transport in Axons

描述（由申请人提供）：α -疱疹病毒是嗜神经性病原体，包括人类病毒水痘带状疱疹病毒（VZV）和单纯疱疹病毒（HSV） 1型和2型，以及动物病毒伪狂犬病毒（PRV）。这些病毒通过轴突定向转运进入外周神经节的感觉神经元细胞体，在那里建立终身潜伏感染。感染通常不会危及健康个体的生命，然而，这些病毒具有跨突触传播的能力，通过电路特定的途径进入大脑。一旦进入大脑，在大多数情况下，脑炎是致命的。我研究的长期目标是确定α -疱疹病毒在神经系统中传播的机制，并确定控制疾病结果的因素。这一建议将重点放在病毒在感觉神经元轴突的传播上。具体:

DESCRIPTION (provided by applicant): Alpha-herpesviruses are neurotropic pathogens that include the human viruses varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2, and the animal virus pseudorabies virus (PRV). These viruses spread into the nervous system by directed axonal transport to sensory neuron cell bodies in peripheral ganglia, where life-long latent infections are established. Infections are typically not life-threatening in healthy individuals, however, these viruses have the capacity to spread trans-synaptically to enter the brain by circuit-specific routes. Once in the brain, the resulting encephalitis is lethal in the majority of cases. The long-term goals of my studies are to determine the mechanisms by which alpha-herpesviruses spread in the nervous system, and to identify the factors governing disease outcome. This proposal will focus on virus spread in the axons of sensory neurons. Specifically:  Using infectious clone mutagenesis methods, viruses will be isolated carrying mutations in the genes encoding each tegument protein  The mutant viruses will be screened for defects in capsid transport in axons by time-lapse tracking of capsids fused to the green-fluorescence protein  Structure/function analysis of tegument proteins required for capsid transport will be initiated In this way, the role of the viral tegument proteins in capsid transport will be definitively tested. These proteins are expected to both tether capsids to microtubule motors and regulate motor activity, as no other class of viral proteins are known to associate with capsids and be exposed to the host cytosol simultaneously. The results of these studies will determine how alpha-herpesviruses move directionally within sensory neurons. This will serve as a first step to identifying the molecular mechanisms of viral transport, and to addressing the larger question of virus spread in the vertebrate nervous system.