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%会经历潜伏病毒的复发性再激活。在眼科社区，它是传染性角膜失明的主要原因，在工业化国家，由于潜伏病毒的再激活。这种病毒的流行和成功被认为存在于通过与人类宿主共同进化而形成的免疫逃避机制中。I型干扰素（IFN）是病毒抵抗这种细胞因子抗病毒作用的主要靶标。我们已经建立了I型干扰素诱导对急性眼部1型单纯疱疹病毒和生殖器2型单纯疱疹病毒感染产生耐药性的必要途径。我们还鉴定了有效和无效的I型IFN转基因，并已开始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外植体培养中HSV-1的再激活。基于我们有希望的初步结果和正在进行的研究，我们提出在体外和体内通过可能独立于传统ifn诱导途径（包括OAS和PKR）的新过程来验证I型和II型ifn阻断HSV-1再激活的假设。为了验证这一假设，我们计划：1)表征I型和II型IFN在TG外植体培养中预防HSV-1再激活的预测协同作用；2)表征I型和II型IFN在体内阻碍HSV-1再激活或阻止进入感觉神经节的病毒运输到达幼稚小鼠角膜的作用；3)表征IFN诱导的组织特异性。在OAS或PKR通路功能失调的中枢神经系统中使用表达I型IFN的转基因小鼠进行抗病毒途径的研究；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的I型IFN转基因治疗修饰的独特蛋白质。预计在实现这一目标的过程中，将在识别阻断HSV-1再激活和在神经系统内传播的途径方面取得重大进展。

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.