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Dynamics of the alphaherpesvirus structure and its impact on targeted intracellular transport.

机译:α疱疹病毒结构的动力学及其对靶向细胞内运输的影响。

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摘要

Several members of the alphaherpesvirus sub-family infect and establish latency within the peripheral nervous system of their natural host. Periodic reactivation from latency can manifest in various forms ranging from mild (herpes labialis) to severe (shingles and encephalitis) disease. Neurotropic herpesviruses depend on longdistance axon transport for the initial establishment of latency in peripheral ganglia (retrograde transport) and for viral spread to exposed body surfaces following reactivation (anterograde transport). The mechanism of alphaherpesvirus transport in neuronal axons is poorly understood and is the focus of this dissertation.Time-lapse fluorescence microscopy was used to image actively translocating viral and cellular components in living neurons, allowing for several aspects of herpesvirus axon transport to be addressed. Here, we demonstrate that herpesviruses use two distinct pathways to move in axons. Following entry, exposure of the capsid to the cytosol results in efficient retrograde transport to neuronal cell bodies. In contrast, progeny viral particles move anterograde in axons following acquisition of virion envelope components and membrane lipids. These findings explain how viral particles are effectively trafficked to either sensory ganglia upon initial infection or peripheral sites of innervation following reactivation, as proper directional targeting in axons is coupled to viral disassembly and assembly processes. The finding that progeny virions use the host secretory pathway to travel to distal axons provides clarity to a long-standing controversy in the field regarding the point at which virions become fully assembled and infectious in neurons. While anterograde viral transport may occur by a constituitive cellular process, retrograde capsid transport is expected to be mediated by a viral component of the capsid transport complex. By identifying the post-entry transport complex and testing the role of several viral proteins in retrograde capsid trafficking, we provide the most likely candidate effectors for dynein-mediated capsid transport.The conservation of axon transport mechanisms was additionally addressed by performing analogous studies on pseudorabies virus (PRV) and herpes simplex virus type-1 (HSV-1). Although subtle differences exist, axon transport processes were largely conserved between these representatives of the two neuroinvasive herpesvirus genera: Simplexvirus (HSV-1) and Varicellovirus (PRV).
机译:甲疱疹病毒亚家族的几个成员在其自然宿主的周围神经系统内感染并建立潜伏期。潜伏期的定期重新激活可以表现为多种形式,从轻度(唇疱疹)到重度(带状疱疹和脑炎)疾病。嗜神经性疱疹病毒依靠长途轴突运输来建立周围神经节中的潜伏期(逆行运输),并在病毒重新激活后(顺行运输)传播到裸露的身体表面。阿尔法疱疹病毒在神经元轴突中的运输机制了解甚少,这是本论文的重点。延时荧光显微镜技术用于对活神经元中病毒和细胞的主动转运进行成像,从而解决了疱疹病毒轴突运输的几个方面。在这里,我们证明疱疹病毒使用两种不同的途径在轴突中移动。进入后,衣壳暴露于细胞质可有效逆行转运至神经元细胞体。相反,后代病毒颗粒在获得病毒体包膜成分和膜脂质后在轴突中顺行移动。这些发现解释了病毒颗粒如何在初次感染时有效地转运到感觉神经节,或者在重新激活后如何有效地转运到神经支配的外周部位,因为轴突中的正确定向靶向与病毒的拆卸和组装过程有关。后代病毒体利用宿主分泌途径行进至远端轴突的发现为该领域中长期存在的争议提供了清晰的证据,这是关于病毒体在神经元中完全组装并具有感染力的观点。尽管顺性病毒运输可能通过组成性细胞过程发生,但逆向衣壳运输预计将由衣壳运输复合体的病毒成分介导。通过鉴定进入后转运复合物并测试几种病毒蛋白在逆向衣壳运输中的作用,我们为动力蛋白介导的衣壳运输提供了最可能的候选效应子。通过对伪狂犬病进行类似研究进一步解决了轴突运输机制的保护问题。病毒(PRV)和1型单纯疱疹病毒(HSV-1)。尽管存在细微的差异,但在两个神经侵入性疱疹病毒属的以下代表之间的轴突运输过程在很大程度上得以保留:单纯疱疹病毒(HSV-1)和水痘病毒(PRV)。

著录项

  • 作者

    Antinone, Sarah.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Biology Microbiology.Biology Virology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 207 p.
  • 总页数 207
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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