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%将经历潜伏病毒的复发性再激活。大多数与HSV-1感染相关的发病率是在宿主的整个生命周期中发生的潜伏病毒的反复再活化的结果。感觉神经元（背根或三叉神经节[TG]）充当潜伏HSV-1的储存库，并且在应激（例如，发烧、创伤）将重新激活。在再活化后，病毒被转运（通过顺行）到接近原始入口的部位，在那里病毒将复制，诱导强烈的炎症反应。与再活化相关的机制尚不清楚。此外，对急性和潜伏病毒感染的免疫应答是复杂的，并且认为适应性和先天免疫系统的多个组分对抗病毒。然而，HSV-1是高度流行的，它的成功被认为是由于它通过与人类宿主共同进化而发展的免疫逃避机制。最近，该实验室专注于I型干扰素（IFN），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。已经产生了在神经系统中表达IFN-α I的转基因小鼠模型和表达许多I型IFN转基因的质粒构建体，以开始阐明宿主用于控制病毒复制的那些机制，重点是神经系统的感染。本申请的目的是解决I型IFN通过诱导包括OAS和PKR的两种IFN刺激基因拮抗HSV-1复制、传播和再活化的假设。为了实现这一目标，我们计划：1）使用体外和体内模型表征抗病毒功效和IFN-刺激性基因级联的诱导，所述IFN-刺激性基因级联是响应HSV-1感染用I型IFN质粒或病毒构建体转染/转导的结果，和2）表征转染后潜伏HSV-1的再活化潜力/使用体外和体内模型用I型IFN转基因转导。预期在实现这些目标的过程中，可以实现对与控制神经系统中的病毒复制和再活化相关的机制的显著洞察。

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.