How herpesviruses sense stress in their hosts

疱疹病毒(例如人类单纯疱疹病毒，HSV-1)的感染始于病毒在进入部位的皮肤细胞中的活跃复制。然后，病毒感染支配病毒复制区域的感觉神经，并在神经细胞中建立潜伏感染。它静静地留在这里，免受主人的防御。为了应对环境或生理压力，神经细胞中的潜伏病毒周期性地重新激活，以复制和再感染皮肤细胞。对于病毒学家来说，建立潜伏期的分子基础长期以来一直是一个既耐人寻味又令人困惑的谜团，这个谜团迄今尚未解开。我们研究的目的是确定HSV-1在宿主受到压力时的感觉。我们的工作不仅将帮助我们了解疱疹病毒如何建立潜伏期并从中重新激活，它还将告诉我们神经系统细胞如何对压力做出反应。我们发现了两种人类蛋白质，它们可能掌握着疱疹病毒潜伏期和重新激活的关键。我们根据京剧中的神话人物命名了鲁曼和张飞。在没有应激的动物体内，痛感神经细胞(HSV潜伏在其中的正是细胞)中的蛋白质似乎抑制了HSV-1的复制，我们认为，它会引导它进入潜伏期。鲁曼能够激活HSV-1基因的表达，我们认为在应激动物的神经细胞中，它可以重新激活潜伏病毒。在我们的研究中，我们发现了一些关于张飞在动物身上可能扮演的正常角色的有趣事情。它似乎与发育中的胚胎中痛觉神经细胞的发育有关。在髓母细胞瘤(一种儿童神经细胞癌)中，没有出现张肺。然而，如果我们现在让这些快速分裂的细胞制造出张飞，它们就会停止分裂，开始看起来像成熟的神经细胞。在接下来的五年里，我们打算调查张飞和鲁曼如何影响HSV-1的复制、潜伏和重新激活。我们还将试图找出这两种蛋白质在正常的、未感染的神经细胞中起什么作用。

Infection with a herpesvirus (the human herpes simplex virus, HSV-1 is an example) begins with active replication of the virus in skin cells at the site of entry. The virus then infects sensory nerves innervating the area of virus replication and establishes a latent infection in nerve cells. Here it quietly remains, protected from the host's defenses. In response to environmental or physiological stress the latent virus in nerve cells reactivates periodically to replicate and reinfect skin cells. The molecular basis for the establishment of latency has long been an intriguing and perplexing puzzle for virologists, a puzzle that has not as yet been solved. The objective of our research is to determine how HSV-1 senses when its host is stressed. Our work will not only help us to understand how herpesviruses establish latency and reactivate from it, it will also tell us how cells of the nervous system respond to stress.We have discovered two human proteins, which may hold the key to herpesvirus latency and reactivation. We have named these proteins Luman and Zhangfei after mythical characters in the Beijing opera.  In pain-sensing nerve cells (the very cells in which HSV becomes latent) in unstressed animals Zhangfei appears to suppress HSV-1 replication and, we think, directs it into latency. Luman is capable of activating HSV-1 gene expression and we think that in the nerve cells of stressed animals it reactivates latent virus.During our studies we have discovered some interesting things about what Zhangfei's normal role in the animal might be. It seems to be involved in the development of the pain-sensing nerve cells in the developing embryo. In medulloblastoma (a childhood nerve cell cancer) no Zhangfei is made. However, if we now get these rapidly dividing cells to make Zhangfei, they stop dividing and start looking like mature nerve cells.Over the next five years we propose to investigate how Zhangfei and Luman influence HSV-1 replication, latency and reactivation. We will also try to find out what the two proteins do in normal, uninfected nerve cells.