Herpes simplex (HSV) egress at synapses

单纯疱疹病毒1型(HSV-1)是阿尔法疱疹病毒亚家族的成员之一，是极少数自然和有效地利用哺乳动物神经系统的病毒之一，并相应地进化出神经元特异性机制，与高度专业化的神经元细胞生物学相互作用。在典型的病程中，阿尔法疱疹病毒感染周围神经系统(PNS)并建立潜伏期。在裂解复制过程中，例如在潜伏期重新激活后，后代病毒颗粒扩散回周围组织，导致反复发生的疱疹病变，也可以扩散到中枢神经系统(CNS)。HSV-1侵入中枢神经系统可导致严重和衰弱的疱疹病毒性脑炎，或可无症状/亚临床。一旦进入中枢神经系统，HSV-1可能会引发神经炎症，并促进神经退行性疾病的发展。为了更好地了解HSV-1传播到中枢神经系统的分子和细胞机制，我们提出了一个创新的方法开发/生物工程目标：开发直接成像神经元突触或附近的病毒颗粒胞吐的方法。这将涉及在有图案的底物上培养初级神经元，以便在指定的位置和方向诱导突触形成。我们将把这种方法与我们建立的活细胞病毒胞吐方法结合起来，以能够成像和研究涉及突触或突触附近的病毒胞吐的细胞生物学因素。阐明HSV-1在神经元中使用的基本细胞生物学过程将增加我们对疱疹病毒如何以及为什么在神经系统传播的理解，有助于识别可用药靶点和开发更好的病毒神经病理学治疗方法，并可能为神经元的细胞生物学提供基本的见解。

Herpes Simplex Virus 1 (HSV-1), a member of the alpha herpesvirus subfamily, is among the very few viruses that naturally and productively exploit the mammalian nervous system, and, accordingly have evolved neuron- specific mechanisms to interact with highly-specialized neuronal cell biology. During the typical course of disease, alpha herpesviruses infect and establish latency in the peripheral nervous system (PNS). During lytic replication, such as following reactivation from latency, progeny virus particles spread back to peripheral tissues, causing recurrent herpetic lesions, and can also spread into the central nervous system (CNS). HSV-1 invasion of the CNS can cause severe and debilitating herpes encephalitis, or can be asymptomatic/sub- clinical. Once in the CNS, HSV-1 may trigger neuroinflammation and contribute to the development of neurodegenerative disease. To better understand the molecular and cellular mechanisms that underlie HSV-1 spread to the CNS, we propose an innovative method development/bioengineering goal: to develop methods to directly image virus particle exocytosis at or near neuronal synapses. This will involve culturing primary neurons on patterned substrates in order to induce synapse formation at defined locations and orientations. We will combine this method with our established live-cell virus exocytosis method to be able to image and study cell biological factors involved in viral exocytosis at or near synapses. Elucidating the basic cell biological processes that HSV-1 uses in neurons will increase our understanding of how and why herpesviruses spread in the nervous system, lead to the identification of druggable targets and development of better therapies for viral neuropathology, and may provide fundamental insights into the cell biology of neurons.