The Neuroimmunology of Viral Infection

描述（由申请人提供）：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%会经历潜伏病毒的复发性再激活。大多数与1型单纯疱疹病毒感染相关的发病是潜伏病毒在宿主一生中反复激活的结果。感觉神经元（背根或三叉神经节[TG]）作为潜伏的HSV-1的储存库，在应激（如发烧、创伤）时将重新激活。在重新激活后，病毒（通过顺行）运输到原始入口附近的位置，在那里病毒将复制，诱导强烈的炎症反应。与再激活相关的机制尚不清楚。此外，对急性和潜伏性病毒感染的免疫反应是复杂的，适应性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，1型单纯疱疹病毒非常普遍，它的成功被认为与它通过与人类宿主共同进化而形成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，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IFN- α I的转基因小鼠模型和表达多种I型IFN转基因的质粒构建物都已被生成，以开始阐明宿主控制以神经系统感染为重点的病毒复制的机制。本应用的目的是解决I型IFN通过诱导两种IFN刺激基因（包括OAS和PKR）拮抗HSV-1复制、传播和再激活的假设。为了实现这一目标，我们计划：1)在体外和体内模型中表征I型IFN质粒或病毒构建物转染/转导后对HSV-1感染的抗病毒功效和诱导IFN刺激基因级联反应；2)在体外和体内模型中表征I型IFN转基因转染/转导后潜伏的HSV-1的再激活电位。预计在实现这些目标的过程中，可以实现对神经系统中与控制病毒复制和再激活相关的机制的重要见解。

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.