Viral determinants in HSV virulence

HSV 毒力的病毒决定因素

基本信息

批准号：
10393596
负责人：
BIN HE
金额：
$ 39.98万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10393596
关键词：
Address Afferent Neurons Amino Acid Motifs Antiviral Agents Antiviral Response Autophagocytosis Autophagosome Biological Blindness Cells Clinical Complex Cornea Country DNA DNA Viruses Data Development Disease Elements Epithelial Epithelial Cells Event Excision Gene Expression Gene Expression Profiling Genes Genetic Determinism Genetic study Golgi Apparatus Growth Herpes encephalitis Herpesvirus 1 Herpetic Keratitis Human Human Herpesvirus 2 Immunity Immunologic Factors Impairment Individual Infection Inflammation Integration Host Factors Interferons Knock-out Lead Lesion Link Lytic Phase Mammalian Cell Mediating Modeling Molecular Mucous Membrane Mus Mutate Nature Nervous system structure Neuraxis Neurons Nucleic Acids Pathway interactions Penetration Peripheral Phenotype Primary Infection Process Production Proteins Recombinants Recurrence Research Signal Transduction Simplexvirus Source TANK-binding kinase 1 TRIM Motif Therapeutic Intervention Tissues Translations Travel Ubiquitination Vaccines Viral Viral Encephalitis Viral Interference Viral Pathogenesis Viral Proteins Virulence Virulence Factors Virus Virus Diseases Virus Replication base cell injury cytokine design gene product in vivo innate immune pathways insight neurovirulence novel novel vaccines pressure prophylactic reactivation from latency recurrent infection response trafficking virus host interaction

项目摘要

Herpes simplex virus (HSV) is the most common cause of infectious blindness and viral encephalitis in the Western countries. Primary or recurrent infection can lead to severe disease, yet no licensed vaccine is available. HSV typically initiates infection in the epithelial cells of mucosa and spreads to sensory neurons where the virus establishes latency. Reactivation from latency occurs intermittently, which is a lifelong source for recurrent lesions. Although viral replication in the mucosa or penetration into the nervous system inflicts damages or inflammation, the disease mechanism is less clear. As a large DNA virus, HSV evokes antiviral responses through the innate immune pathways that regulate TANK-binding kinase 1, a key factor required to activate cytokine expression and autophagy in mammalian cells. Remarkably, while the interferon- stimulated gene (STING) drives the cytokine response the tripartite motif protein 23 (TRIM23) serves to mediate autophagy. Despite such regulatory control, HSV is able to compromise host restrictions, which depends on an HSV virulence factor γ134.5. A central hypothesis of this proposal is that HSV differentially reprograms host immunity, where a dynamic interplay between viral and cellular factors may determine HSV spread, virulence and inflammation. Current effort is directed to decipher mechanisms of HSV pathogenesis. Several aspects of HSV infection will be investigated in a multi- faceted approach. Accordingly, recombinant HSV will be generated to determine the nature of HSV interactions with the innate immune factors in epithelial and neuronal cells. This will dissect elements pertinent to viral interference of the nucleic acid sensing complexes and autophagy machineries. Furthermore, genetic studies will explore viral features relevant to ocular replication, spread and neurovirulence. In parallel, gene expression analysis will assesses ocular and neuoinflammation. Collectively, these studies will provide an insight into genetic determinants of HSV virulence, which may inform design of novel antiviral therapeutics or vaccines.

单纯疱疹病毒（HSV）是导致传染性失明的最常见原因在西方国家，病毒性脑炎可导致原发性或复发性感染。严重的疾病，但尚无获得许可的疫苗通常会引发 HSV 感染。粘膜上皮细胞并传播到感觉神经元，病毒在那里建立潜伏期，从潜伏期重新激活是间歇性的，这是一个终生的过程。尽管病毒在粘膜中复制或渗透到复发性病变的来源。神经系统损伤或炎症，发病机制较少作为一种大型 DNA 病毒，HSV 通过先天免疫引起抗病毒反应。调节 TANK 结合激酶 1 的途径，这是激活细胞因子所需的关键因素值得注意的是，干扰素在哺乳动物细胞中的表达和自噬。刺激基因 (STING) 驱动细胞因子反应三联基序蛋白 23 (TRIM23) 可以介导自噬，尽管有这样的监管控制，HSV 仍能够介导自噬。妥协宿主限制，这取决于 HSV 毒力因子 γ134.5 A。该提议的中心假设是 HSV 差异性地重新编程宿主免疫，病毒和细胞因素之间的动态相互作用可能决定 HSV 当前的努力旨在破译其传播、毒力和炎症的机制。 HSV 发病机制将在多个方面进行研究。因此，将产生重组HSV来确定 HSV 与上皮和神经元先天免疫因子相互作用的性质这将剖析与核酸传感的病毒干扰相关的元素。此外，遗传学研究将探索病毒。与眼部复制、传播和神经毒力相关的特征。表达分析将共同评估眼部和神经炎症。研究将深入了解 HSV 毒力的遗传决定因素，这可能为新型抗病毒疗法或疫苗的设计提供信息。