Using herpes simplex virus as a tool to interrogate fundamental cellular stress pathways.

对病毒如何与宿主细胞相互作用的研究已经发现了许多保守的宿主过程。事实上，单纯疱疹病毒（HSV）等病毒已经与人类共同进化了数千年，因此HSV是研究宿主功能的绝佳工具。一个新兴的新范式，部分基于我们的贡献，是细胞识别病毒感染作为细胞稳态的破坏。因此，长期计划的愿景是使用HSV作为工具来阐明细胞如何在分子水平上识别和响应压力的基本方面。在最近的一次筛选中，我们发现了即时早期HSV蛋白ICP 0和细胞蛋白G3 BP 2之间的一种新的相互作用。ICP 0是一种多功能蛋白，通过破坏宿主的内在和先天反应，使病毒能够部分复制。 G3 BP 2是RNA应激颗粒（SGs）的重要组成部分，其在感知细胞应激时形成，并且与多种疾病相关。最近的研究表明，许多病毒利用或阻止SG的形成，表明SG在识别和介导病毒感染的结果中发挥重要作用。我们的初步研究表明，ICP 0在感染早期起作用以阻断SG的形成，因为有效的SG形成仅在感染缺乏ICP 0表达的HSV后可见。本提案的目的是利用我们在分子病毒学、分子生物学和病毒-宿主相互作用方面的专业知识，研究触发SG形成的HSV感染的早期事件，并确定SG，特别是G3 BP 2，如何调节病毒感染。我们还将评估ICP 0和G3 BP 2之间的相互作用对G3 BP 2的SG依赖性和SG非依赖性功能的重要性。利用我的实验室内完善和可用的资源，技术和基础设施，这些研究将增强我们对基本细胞过程的理解，例如在破坏稳态时诱导有效的细胞应激反应。由于这些反应是整个生物体成功的基础，因此这些基础知识的产生将导致对许多疾病的基本机制的更深入理解。

Studies of how viruses interact with host cells have led to the discovery of many conserved host processes. Indeed, viruses such as Herpes simplex virus (HSV) have co-evolved with humans for thousands of years, thus HSV is an excellent tool to study host functions. An emerging new paradigm, based in part on our contributions, is that cells recognize viral infection as a disruption of cellular homeostasis. Thus, the long-term program vision is to use HSV as a tool to elucidate fundamental aspects of how cells recognize and respond to stress at the molecular level. In a recent screen, we uncovered a novel interaction between the immediate early HSV protein ICP0 and the cellular protein G3BP2. ICP0 is a multifunctional protein that enables virus replication in part by subverting host intrinsic and innate responses.  G3BP2 is an essential component of RNA stress granules (SGs), which form upon sensing of cellular stress and which have been associated with a variety of diseases. Recent studies indicate that many viruses either exploit or block SG formation, indicating that SGs play an important role in recognizing and mediating the outcome of a virus infection. Our preliminary studies suggest that ICP0 functions early during infection to block the formation of SGs, as efficient SGs formation is only visible following infection of HSV lacking ICP0 expression. The objectives of this proposal are to use our expertise in molecular virology, molecular biology and virus-host interactions to investigate the early events of HSV infection that trigger SG formation and to determine how SGs, and in particular G3BP2, modulate virus infection. We will also evaluate the importance of the interaction between ICP0 and G3BP2 on SG-dependent and SG-independent functions of G3BP2. Using resources, techniques and infrastructure that are well-established and available within my laboratory, these studies will enhance our understanding of basic cellular processes, such as induction of effective cell stress responses upon disruption of homeostasis. As these responses underlie the success of an organism as a whole, the generation of such fundamental knowledge will lead to a greater understanding of the basic mechamisms underlying many diseases.