Alpha-Herpesvirus Transport on Axons

描述（由申请人提供）：神经侵袭性疱疹病毒从感觉神经元传播到眼睛、大脑或从母亲传播给新生儿是与这类病原体感染相关的发病率和死亡率的主要原因。1型单纯疱疹病毒（HSV-1）和伪狂犬病毒（PRV）是神经侵袭性疱疹病毒（单纯疱疹病毒和水痘病毒）两属的代表性成员，均属于α -疱疹病毒亚科。这两种病毒在周围神经系统的感觉神经元中建立终身潜伏感染，并且都是实验室使用的建立模型。在这一建议中，我们利用我们在感染性克隆诱变和活细胞病毒跟踪方法方面的优势来解决HSV-1和PRV在感觉神经元内传播的机制。病毒转运到潜伏部位和再激活后转运到周围神经支配组织都是病毒感染周期的关键，这两个阶段的感染都是用培养的感觉神经元模拟的，并在动物身上进行检测，以研究病毒在细胞内转运的机制。此外，新的证据表明，非常大的疱疹病毒被膜蛋白VP1/2负责衣壳的细胞内运输，并采用了新的工具来解剖病毒沿微管运输的机制。

DESCRIPTION (provided by applicant): Spread of neuroinvasive herpesviruses from sensory neurons to the eye, brain or from mother to newborn are leading causes of morbidity and mortality associated with infections by this class of pathogens. Herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) are representative members of the two genuses of neuroinvasive herpesviruses (simplexviruses & varicelloviruses), both belonging to the alpha-herpesvirus subfamily. Both viruses establish life-long latent infections in sensory neurons of the peripheral nervous system, and both are established models for use in the laboratory. In this proposal, we leverage our strengths in infectious clone mutagenesis and live-cell viral tracking methods to address the mechanisms of HSV-1 and PRV spread within sensory neurons. Viral transport to the site of latency and transport following reactivation to peripheral innervated tissues are both critical to the viral infectious cycle, and both of these stages of infection are modeled using cultured sensory neurons and examined in animals to investigate the mechanisms of virus intracellular trafficking. In addition, new evidence is provided indicating that the very large herpesvirus tegument protein, VP1/2, is responsible for intracellular transport of capsids, and new tools for dissecting the mechanism of viral transport along microtubules are employed.