The Neuroimmunology of Viral Infection

描述（由申请人提供）：1型单纯疱疹病毒（HSV-1）是一种临床相关病原体，感染1.5亿至2亿美国人，其中20%的人将经历潜伏病毒的复发性再激活。在眼科界，由于潜伏病毒的再活化，它是工业化世界中感染性角膜失明的主要原因。这种病毒的流行和成功被认为是由于通过与人类宿主的共同进化而形成的免疫逃避机制。I型干扰素（IFN）是病毒对抗对这种细胞因子的抗病毒作用的抗性的主要靶标。我们已经建立了I型IFN诱导的急性眼部HSV-1和生殖器HSV-2感染的抗性所必需的途径。我们还鉴定了有效和无效的I型IFN转基因，并开始了发现蛋白质组学方法以鉴定由有效的I型IFN转基因特异性修饰的蛋白质。初步数据还表明I型IFN和IFN-γ（II型IFN）转基因能够部分或完全阻断TG外植体培养物中的HSV-1再活化。基于我们有希望的初步结果和正在进行的研究，我们建议测试的假设，I型和II型干扰素块HSV-1再激活在体外和体内通过新的过程，可能是独立的传统的干扰素诱导途径，包括OAS和PKR。为了验证这一假设，我们计划：1）表征I型和II型IFN在TG外植体培养物中预防HSV-1再活化中的预测协同作用，2）表征I型和II型IFN在体内阻碍HSV-1再活化或阻断置于感觉神经节中的病毒运输到达幼稚小鼠角膜中的作用，3）使用在中枢神经系统中表达I型IFN的转基因小鼠表征IFN诱导的抗病毒途径的组织特异性性质，所述转基因小鼠具有功能失调的OAS或PKR途径，以及4）使用发现和功能蛋白质组学，鉴定和表征原位转染后三叉神经节中有效I型IFN转基因处理修饰独特蛋白质。预计在实现这一目标的过程中，将在鉴定参与阻断HSV-1在神经系统内再活化和传播的途径方面实现重要的见解。

DESCRIPTION (provided by applicant): Herpes simplex virus type 1 (HSV-1) is a clinically relevant pathogen infecting 150 to 200 million Americans in which 20% will experience recurrent reactivation of latent virus. In the ophthalmic community, it is the leading cause of infectious corneal blindness in the industrialized world as a result of reactivation of latent virus. The prevalence and success of this virus is thought to reside in the immune evading mechanisms that have developed through co-evolution with the human host. Type I interferons (IFN) are a principal target of the virus countering resistance to the anti-viral effects of this cytokine. We have established pathways necessary for type I IFN-induced resistance to acute ocular HSV-1 and genital HSV-2 infection. We have also identified efficacious and non-efficacious type I IFN transgenes and have begun a discovery proteomics approach to identify proteins specifically modified by the efficacious type I IFN transgene. Preliminary data also suggest type I IFN and IFN-gamma (type II IFN) transgenes are able to partially or completely block HSV-1 reactivation in TG explant cultures. Based on our promising preliminary results and ongoing study, we propose to test the hypothesis that type I and type II IFNs block HSV-1 reactivation in vitro and in vivo through novel processes that may be independent of conventional IFN-inducible pathways including OAS and PKR. To test this hypothesis, we plan to: 1) characterize the predicted synergistic effect of type I and type II IFN in the prevention of HSV-1 reactivation in TG explant cultures, 2) characterize the effect of type I and type II IFN in hindering HSV-1 reactivation in vivo or in blocking the trafficking of virus placed into the sensory ganglion from reaching the cornea of naive mice, 3) characterize the tissue-specific nature of IFN- inducible, anti-viral pathways using transgenic mice expressing type I IFN in the central nervous system that have dysfunctional OAS or PKR pathways, and 4) using discovery and functional proteomics, identify and characterize unique proteins modified by efficacious type I IFN transgene treatment in trigeminal ganglia following in situ transfection. It is anticipated that in achieving this goal, significant insight will be accomplished in the identification of pathways involved in blocking HSV-1 reactivation and spread within the nervous system.