The Neuroimmunology of Viral Infection

描述(申请人提供)：根据血清阳性率，1.5亿至2亿美国人潜伏感染1型单纯疱疹病毒(HSV-1)，其中20%将经历潜伏病毒的反复激活。与HSV-1感染相关的大多数发病率是由于潜伏病毒在宿主的整个生命周期中反复重新激活的结果。感觉神经元(背根或三叉神经节[TG])是潜伏的HSV-1的储存库，在应激(如发烧、创伤)时会重新激活。一旦重新激活，病毒被(通过顺行)传播到原始入口附近的位置，在那里病毒将复制，引发强烈的炎症反应。与重新激活相关的机制(S)尚不清楚。此外，对急性和潜伏病毒感染的免疫反应是复杂的，适应性免疫系统和先天免疫系统的多个组成部分被认为可以对抗病毒。然而，HSV-1非常普遍，它的成功被认为与它通过与人类宿主共同进化而发展起来的免疫逃避机制有关。最近，该实验室专注于I型干扰素(IFN)，这是一种有效的抗病毒细胞因子家族，可在应对包括HSV-1在内的病毒感染时分泌。在神经系统中表达干扰素-αI的转基因小鼠模型和表达I型干扰素转基因基因的质粒构建物都已被建立，以开始阐明宿主用来控制病毒复制的机制，重点是神经系统感染。本应用的目的是解决这一假设，即I型IFN通过诱导两个干扰素刺激基因包括OAS和PKR来对抗HSV-1的复制、传播和重新激活。为了实现这一目标，我们计划：1)利用体外和体内模型研究I型干扰素载体或病毒载体对HSV-1感染的抗病毒效果和诱导干扰素刺激基因级联反应；2)利用体外和体内模型研究I型干扰素转基因感染后潜伏的HSV-1的再激活潜力。预计在实现这些目标的过程中，可以对神经系统中控制病毒复制和重新激活的机制(S)有重大的洞察力。

DESCRIPTION (provided by applicant): Based on the seroprevalence rates, between 150 and 200 million Americans are latently infected with herpes simples virus type 1 (HSV-1) of which 20% will experience recurrent reactivation of latent virus. Most of the morbidity associated with HSV-1 infection is a result of repeated reactivation of latent virus that occurs throughout the lifetime of the host. Sensory neurons (dorsal root or trigeminal ganglion [TG]) serve as a reservoir for latent HSV-1 and upon stress (e.g., fever, trauma) will reactivate. Upon reactivation, the virus is transported (via anterograde) to sites proximal to the original portal of entry where the virus will replicate inducing a strong inflammatory response. The mechanism(s) associated with reactivation are not understood. Moreover, the immune response to acute and latent virus infection is complex and multiple components of both the adaptive and innate immune systems are thought to counter the virus. However, HSV-1 is highly prevalent and its success is thought to reside with the immune evading mechanisms that it has developed through co-evolution with the human host. Recently, this lab has focused on type I interferons (IFN), a family of potent anti-viral cytokines secreted in response to viral infection including HSV-1. A transgenic mouse model expressing IFN-alpha I in the nervous system and plasmid constructs expressing a number of type I IFN transgenes have all been generated to begin to elucidate those mechanisms utilized by the host to control viral replication focusing on infections of the nervous system. The goal of this application is to address the hypothesis that type I IFNs antagonize HSV-1 replication, spread, and reactivation through the induction of two IFN stimulatory genes including OAS and PKR. To achieve this goal, we plan to: 1) characterize the anti-viral efficacy and the induction of the IFN-stimulatory gene cascade as a result of transfection/transduction with type I IFN plasmid or viral constructs in response to HSV-1 infection using in vitro and in vivo models and 2) characterize the reactivation potential of latent HSV-1 following transfection/transduction with type I IFN transgenes using in vitro and in vivo models. It is anticipated that in accomplishing these aims, significant insight into the mechanism(s) associated with controlling viral replication and reactivation in the nervous system can be achieved.