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

• 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
• 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

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(申请人提供)：我们将研究单纯疱疹病毒1型(HSV-1)的两种细胞受体，疱疹病毒进入介体(HSV-1)和Nectin-1在角膜感染和利用小鼠敲除(KO)建立这些受体的潜伏期中的重要性。细胞培养和体内小鼠单纯疱疹病毒感染模型的研究表明，HVEM和Nectin-1在介导HSV进入方面是最有效的，在HSV的发病机制中也是最重要的。HSV-1的重新激活可能导致口腔溃疡或更严重的疾病，包括脑炎和疱疹间质角膜炎(HSK)的复发。HSK的确切发病机制尚不完全清楚，但已知的致病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，并研究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)中起HSV-1进入介质的作用。为了全面了解HSV-1的发病机制和发展治疗方法，了解HSV-1在眼睛中的靶组织是必不可少的。我们提出的研究将为进一步的研究奠定基础，以确定特定细胞类型的感染，如免疫系统的细胞，是否在眼睛中的HSV发病中起重要作用。通过确定眼睛感染中HSV感染的确切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。这种靶向治疗可能会减轻原发感染和/或减少炎性免疫细胞，从而防止包括HSK、失明和脑炎在内的毁灭性后遗症。在目标1中，我们将通过确定HSV-1原发感染是否需要HVEM和/或Nectin-1来表征HSV-1在角膜原发感染中的作用。我们还将评估输入病毒载量在带状疱疹病毒病发展中的重要性，并确定在原发HSV-1感染期间眼睛和TG中的哪些细胞被感染，以及这些细胞是否表达HSV-1和/或Nectin-1。在目标2中，我们将确定HSV潜伏感染三叉神经节是否需要HVEM和/或Nectin-1。 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间质角膜炎(HSK)。了解这些受体在HSK中的作用以及它们是如何导致疾病的，将为开发治疗HSK的新疗法提供洞察力，HSK是美国最常见的角膜失明原因。