Role of Host Cell Factors in Herpes Simplex Virus (HSV) Keratitis

宿主细胞因子在单纯疱疹病毒 (HSV) 角膜炎中的作用

基本信息

批准号：
8029319
负责人：
Richard M Longnecker
金额：
$ 22.88万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8029319
关键词：
Adult Animals Attenuated Blindness Brain Cell Culture Techniques Cell Surface Receptors Cells Clinical Conjunctivitis Cornea Corneal Stroma Development Disease Disease model Dose Encephalitis Epithelial Epithelial Cells Epithelium Eye Eye Infections Fluorescence Microscopy Foundations Ganglia Gray unit of radiation dose Heparitin Sulfate Herpes Simplex Infections Herpes encephalitis Herpesviridae Herpesviridae Infections Herpesvirus 1 Herpetic Keratitis Hippocampus (Brain)Human Human Herpesvirus 2 Immune Immune response Immune system Infection Inflammation Mediators Inflammatory Inorganic Sulfates Keratitis Knock-out Knockout Mice Lead Letters Mediating Mediator of activation protein Modeling Mus Neuroglia Neurons Oral Ulcer Outcome Study PVRL1 Pathogenesis Peripheral Play Proteins Recurrence Recurrent disease Research Role Scientist Simplexvirus Site Skin Spinal Cord Spinal Ganglia Structure of trigeminal ganglion Therapeutic Tissues Treatment Protocols Unspecified or Sulfate Ion Sulfates Vagina Vascularization Viral Viral Antigens Viral Load result Virus Virus Diseases Virus Latency Work cell type corneal epithelium experience in vivo in vivo Model insight latent infection mouse model nectin neurotropic novel therapeutics novel virus oral lesion prevent receptor receptor expression receptor function virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): We will study the importance of two cellular receptors for herpes simplex 1 (HSV-1), herpes viral entry mediator (HVEM) and nectin-1, in the infection of the cornea and the establishment of latency by using mice knocked out (KO) for these receptors. Studies in cell culture and in vivo murine models of HSV infection indicate that HVEM and nectin-1 are the most efficient at mediating entry and most important in HSV pathogenesis. Reactivation of HSV-1 can lead to recurrent disease in the form of oral ulcers or more serious disease including encephalitis and herpes stromal keratitis (HSK). The precise mechanism of HSK pathogenesis is not fully understood, but factors known to contribute to disease include viral replication and the resulting immune response. We plan to study the outcome of corneal inoculation as well as examine which receptors function as HSV-1 entry mediators in susceptible tissues (corneal epithelium, corneal stroma, TG neurons, non-neuronal cells of the TG, immune cells, etc.). To fully understand disease pathogenesis and develop therapeutics, it is essential to understand the target tissues of HSV-1 in the eye. Our proposed studies will lay the foundation for further studies to determine whether infection of specific cell types, such as cells of the immune system, are important in HSV pathogenesis in the eye. By determining the precise cells infected by HSV in an ocular infection and the receptors utilized by the virus, novel treatment regimens can be developed that target those receptors. Such targeted therapies might attenuate primary infection and/or reduce inflammatory immune cells thereby preventing devastating sequelae including HSK, blindness, and encephalitis. In Aim 1, we will characterize the role of HVEM and nectin-1 in primary HSV-1 infection of the cornea by determining whether HVEM and/or nectin-1 are required for primary HSV-1 infection of the cornea. We will also evaluate the importance of input viral load on the development of zosteriform disease and determine which cells in the eye and TG are infected during primary HSV-1 infection and whether or not those cells are expressing HVEM and/or nectin-1. In Aim 2, we will determine whether HVEM and/or nectin-1 are necessary for HSV latent infection of the trigeminal ganglion. PUBLIC HEALTH RELEVANCE: Our specific aims are to identify the importance of the cellular receptors, HVEM and nectin-1, for HSV-1 infection of the eye. But more importantly how the use of these receptors contribute to herpes stromal keratitis (HSK). An understanding of the role for these receptors in HSK and how they contribute to disease will provide insight for the development of novel therapeutics for the treatment HSK which is the most frequent cause of corneal blindness in the US.

描述（由申请人提供）：我们将研究单纯疱疹病毒 1 (HSV-1)、疱疹病毒进入介质 (HVEM) 和 nectin-1 的两种细胞受体在角膜感染和建立潜伏期中的重要性使用这些受体被敲除（KO）的小鼠。 HSV 感染的细胞培养和体内小鼠模型研究表明，HVEM 和 nectin-1 在介导进入方面最有效，并且在 HSV 发病机制中最重要。 HSV-1 重新激活可导致口腔溃疡或更严重的疾病复发，包括脑炎和疱疹性基质角膜炎 (HSK)。 HSK 发病机制的确切机制尚不完全清楚，但已知导致疾病的因素包括病毒复制和由此产生的免疫反应。我们计划研究角膜接种的结果，并检查哪些受体在易感组织（角膜上皮、角膜基质、TG 神经元、TG 的非神经元细胞、免疫细胞等）中充当 HSV-1 进入介质。为了充分了解疾病发病机制并开发治疗方法，了解 HSV-1 在眼睛中的靶组织至关重要。我们提出的研究将为进一步研究奠定基础，以确定特定细胞类型（例如免疫系统细胞）的感染是否在眼睛中的 HSV 发病机制中重要。通过确定眼部感染中 HSV 感染的精确细胞和病毒利用的受体，可以开发针对这些受体的新治疗方案。此类靶向治疗可能会减弱原发感染和/或减少炎症免疫细胞，从而预防包括 HSK、失明和脑炎在内的破坏性后遗症。在目标 1 中，我们将通过确定角膜原发性 HSV-1 感染是否需要 HVEM 和/或 nectin-1 来表征 HVEM 和 nectin-1 在角膜原发性 HSV-1 感染中的作用。我们还将评估输入病毒载量对带状疱疹样疾病发展的重要性，并确定在原发性 HSV-1 感染期间眼睛和 TG 中的哪些细胞受到感染，以及这些细胞是否表达 HVEM 和/或 nectin-1。在目标 2 中，我们将确定 HVEM 和/或 nectin-1 是否是三叉神经节 HSV 潜伏感染所必需的。公共卫生相关性：我们的具体目标是确定细胞受体 HVEM 和 nectin-1 对于眼睛 HSV-1 感染的重要性。但更重要的是这些受体的使用如何导致疱疹性基质角膜炎（HSK）。了解这些受体在 HSK 中的作用以及它们如何导致疾病，将为开发治疗 HSK 的新疗法提供见解，HSK 是美国角膜失明的最常见原因。