Herpes Simplex Virus Utilizes the Large Secretory Vesicle Pathway for Anterograde Transport of Tegument and Envelope Proteins and for Viral Exocytosis from Growth Cones of Human Fetal Axons
Herpes Simplex Virus Utilizes the Large Secretory Vesicle Pathway for Anterograde Transport of Tegument and Envelope Proteins and for Viral Exocytosis from Growth Cones of Human Fetal Axons
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DOI：
10.1128/jvi.01579-08
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发表时间：
2009-04-01
影响因子：
5.4
通讯作者：
Cunningham, Anthony L.
中科院分区：
文献类型：
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作者：
Miranda-Saksena, Monica;Boadle, Ross A.;Cunningham, Anthony L.
单纯疱疹病毒（HSV-1）的轴突转运是病毒在宿主周围神经系统感染和传播所必需的。因此，该病毒可能利用神经元中现有的主动转运和靶向机制进行病毒组装并从神经元扩散到皮肤。在本研究中，我们使用透射免疫电镜研究了参与HSV-1被膜和包膜蛋白顺行轴突运输的囊泡的性质和起源，以及生长锥中部分和完全包裹的衣壳周围的囊泡。本研究旨在阐明病毒在人胎儿背根神经节神经元轴突的组装和退出机制。我们证明了病毒被膜和包膜蛋白可以独立于病毒衣壳在轴突中移动，并通过两种类型的运输囊泡——管状囊泡膜结构和大的致密覆盖囊泡——被运输到轴突末端。这些囊泡和膜载体来源于反式高尔基网络（TGN），含有参与轴突分泌和胞外通路的关键蛋白，如Rab3A、SNAP-25、GAP-43和kinesin-1。在生长锥完全和部分包裹的衣壳以及细胞外病毒粒子上也观察到这些蛋白。我们的发现为未包膜衣壳在轴突中与包膜和被膜蛋白分离运输的亚组装模型提供了进一步的证据，最终病毒组装发生在轴突末端。我们假设HSV-1衣壳内陷被膜和包膜tgn衍生囊泡，并利用胞吐的大分泌囊泡途径从轴突排出。
Axonal transport of herpes simplex virus (HSV-1) is essential for viral infection and spread in the peripheral nervous system of the host. Therefore, the virus probably utilizes existing active transport and targeting mechanisms in neurons for virus assembly and spread from neurons to skin. In the present study, we used transmission immnunoelectron microscopy to investigate the nature and origin of vesicles involved in the anterograde axonal transport of HSV-1 tegument and envelope proteins and of vesicles surrounding partially and fully enveloped capsids in growth cones. This study aimed to elucidate the mechanism of virus assembly and exit from axons of human fetal dorsal root ganglia neurons. We demonstrated that viral tegument and envelope proteins can travel in axons independently of viral capsids and were transported to the axon terminus in two types of transport vesicles, tubulovesicular membrane structures and large dense-cored vesicles. These vesicles and membrane carriers were derived from the trans-Golgi network (TGN) and contained key proteins, such as Rab3A, SNAP-25, GAP-43, and kinesin-1, involved in the secretory and exocytic pathways in axons. These proteins were also observed on fully and partially enveloped capsids in growth cones and on extracellular virions. Our findings provide further evidence to the subassembly model of separate transport in axons of unenveloped capsids from envelope and tegument proteins with final virus assembly occurring at the axon terminus. We postulate that HSV-1 capsids invaginate tegument- and envelope-bearing TGN-derived vesicles and utilize the large secretory vesicle pathway of exocytosis for exit from axons.