HPSE in Ocular Herpes Infection

HPSE 在眼部疱疹感染中的应用

• 批准号: 9761531
• 负责人: DEEPAK SHUKLA
• 金额: $ 39.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761531
• 关键词: Adverse effects; Animal Model; Antiinflammatory Effect; Antiviral Agents; Area; Basement membrane; Binding; Biological Assay; Blindness; CRISPR/Cas technology; Cell Nucleus; Cells; Chromosome Deletion; Clinical; Complex; Cornea; Corneal Diseases; Corneal Ulcer; Data; Development; Disease; Endothelium; Environment; Enzyme-Linked Immunosorbent Assay; Enzymes; Epithelial; Epithelial Cells; Extravasation; Eye Infections; Flow Cytometry; Genetic Transcription; Growth; Growth Factor; Heparanase inhibitors; Heparitin Sulfate; Herpesviridae Infections; Herpesvirus 1; Herpetic Keratitis; Human; Immune; Immunofluorescence Immunologic; Immunohistochemistry; Infection; Inflammation; Investigation; Keratitis; Knock-out; Knockout Mice; Laboratories; Leukocytes; Lymphoid; Molecular; Mus; Myelogenous; NF-kappa B; Nuclear; Pain; Pathogenicity; Pathology; Pharmacology; Plaque Assay; Population; Production; Protein Biosynthesis; Proteins; Proteomics; Publishing; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; Severities; Signal Transduction; Simplexvirus; Structure of trigeminal ganglion; Symptoms; Systems Biology; Therapeutic; Tissues; Ulcer; Up-Regulation; Vascular Permeabilities; Viral; Viral load measurement; Virulence Factors; Virus; Virus Diseases; Vision; Western Blotting; angiogenesis; base; corneal epithelium; cytokine; experimental study; heparanase; immunological status; lymph nodes; mouse model; neovascularization; novel drug class; promoter; response; sugar; sulfurtransferase; transcription factor; transmission process

The major clinical complications associated with herpes simplex virus -1 (HSV-1) infection of the eye include corneal ulcers, severe pain, inflammation, loss of corneal avascularity, and vision loss. Antiviral agents alone often fail to correct the problems because many of the disease symptoms may be signaled by infection but then regulated more directly by host molecules. This proposal studies, human heparanase (HPSE), a host enzyme that may potentially regulate both, virus growth and disease manifestations in the cornea. HPSE is a heparan sulfate (HS) endoglycosidase whose levels correlate directly with the breakdown of epithelial and endothelial basement membrane barriers, increased vascular permeability and leukocyte extravasation, and liberation of HS-bound cytokines and growth factors promoting angiogenesis and inflammation in the surrounding areas. The PI’s laboratory has recently observed a significant increase in HPSE expression and higher enzymatic activity upon HSV infection of human corneal cells, cultured human corneas, and animal models of ocular infection and demonstrated its significance in viral spread and transmission. In murine corneas HPSE upregulation directly contributes to corneal disease pathologies including ulceration, inflammation and neovascularization. In addition, we unexpectedly found that HPSE knockout cells show a severe deficiency in virus production. Therefore, based on our newly generated preliminary results we hypothesize an important regulatory role for HPSE in HSV-1 transcription and propose to establish HPSE as a key host virulence factor. We propose that activated HPSE directly adds to the severity of herpetic diseases including tissue damage and promotes viral infection and reactivation. This proposal will focus on understanding the HPSE driven mechanisms that contribute to HSV-1 growth in the cornea and demonstrating the antiviral/anti-inflammatory effects of HPSE inhibition or chromosomal deletion. Three Aims are proposed. First Aim will establish the molecular basis behind the loss of HSV-1 infection in cells lacking HPSE. It is based on our hypothesis that HPSE through its nuclear localization and complex set of interactions promote HSV-1 transcription. Second Aim will determine the significance of HPSE in HSV-1 infection of the murine cornea. This Aim will use a HPSE knockout mouse model to prove our hypothesis that HPSE is a host virulence factor that promotes HSV-1 infection in the cornea, drives tissue damage and disease pathologies, and facilitates viral spread to and return from the trigeminal ganglia (TG) during reactivation. The third and final Aim will determine the therapeutic benefits of an HPSE inhibitor against HSV-1 infection of the cornea. This Aim will prove our hypothesis that pharmacological inhibition of HPSE will result in unprecedented therapeutic benefits including quick resolution of infection and corneal inflammation. Successful conclusion of our study will help establish a brand new role for HPSE as a host virulence factor and identify new factors that help promote its pathogenic activities in the cornea. Our results will significantly enhance our understanding of HPSE functions and herpetic disease mechanisms, and accelerate new strategies to control ocular infection.

与眼睛的单纯疱疹病毒-1（HSV -1）感染有关的主要临床并发症包括 角膜溃疡，严重的疼痛，炎症，角膜丧失和视力丧失 通常无法纠正问题 然后由宿主分子更直接地调节。 可能调节角膜中病毒生长和疾病表现的酶。 硫酸乙酰肝素（HS）内糖苷酶，其水平与上皮分解直接相关 室内地下室膜屏障，血管渗透性增加和白细胞渗出，并 解放了HS结合的细胞因子和增长因子促进子的启动子和炎症 周围地区。 人角膜细胞，培养的人角膜和动物的HSV感染后，酶活性较高 眼部感染的模型表现出其在病毒传播中的重要性 角膜HPSE上调直接有助于角膜疾病病理，包括溃疡， 炎症和新生血管化。 因此，基于新生成的预赛，病毒的严重缺乏 假设HPSE在HSV-1转录中扮演重要的规律性角色，并建议将HPSE建立为 我们提出的一个关键宿主病毒因素直接激活HPSE 包含组织损伤并促进病毒感染和重新激活。 了解HPSE驱动的机制，这些机制有助于角膜中HSV-1的增长 证明了抑制或染色体缺失的抗抗血液/抗炎作用。 目的是支撑的。 缺乏HPSE。 相互作用促进HSV-1转录。 鼠角膜的感染。 HPSE是一种宿主病毒因子，它在角膜中感染HSV-1，驱动组织损伤和 疾病的病理，并促进病毒传播到三叉神经节（TG）期间的病毒传播 重新激活。 角膜的HSV-1感染。 将带来前所未有的治疗益处，包括快速解决感染和角膜 炎症。 病毒因素并确定有助于促进其角膜的致病活性的新因素。 将大大增强我们对HPSE功能和疱疹疾病机制的理解，并 加速控制眼部感染的新策略。