Alpha-Herpesvirus Transport on Axons

描述（由申请方提供）：神经侵袭性疱疹病毒从感觉神经元传播至眼、脑或从母亲传播至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。单纯疱疹病毒1型（HSV-1）和伪狂犬病病毒（PRV）是神经侵袭性疱疹病毒（单纯疱疹病毒和水痘病毒）的两个属的代表成员，两者都属于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，并且两者都是用于实验室的已建立模型。在这个提议中，我们利用我们在感染性克隆诱变和活细胞病毒追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。病毒运输到潜伏期和运输后的周围神经支配的组织激活的网站都是至关重要的病毒感染周期，这两个阶段的感染是使用培养的感觉神经元建模，并在动物中检查，以研究病毒细胞内运输的机制。此外，提供了新的证据表明，非常大的疱疹病毒被膜蛋白，VP 1/2，是负责衣壳的细胞内运输，和新的工具解剖的机制，病毒运输沿着微管。 公共卫生相关性：神经侵入性α-疱疹病毒是许多严重疾病的病原体，包括带状疱疹、脑炎、新生儿感染和疱疹性角膜炎（在美国和其他工业化国家中感染性失明的主要原因）。该提案的重点是了解疱疹病毒在神经系统内传播并导致疾病的细胞机制，长期目标是开发新的治疗方法来干预疾病进展。

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. PUBLIC HEALTH RELEVANCE: Neuroinvasive alpha-herpesviruses are the causative agents of a number of severe diseases including shingles, encephalitis, neonatal infections and herpes keratitis (the leading cause of infectious blindness in the USA and other industrialized nations). This proposal focuses on understanding the cellular mechanisms used by herpesviruses to spread within the nervous system and cause disease, with the long term goal of developing new treatments to intervene with disease progression.