Viral determinants in HSV virulence

HSV 毒力的病毒决定因素

• 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
• 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

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 以及西方国家的病毒性脑炎。原发性或复发性感染可导致 病情严重，但尚未获得许可的疫苗。 HSV 通常在以下部位引发感染： 粘膜上皮细胞并传播到感觉神经元，病毒在那里 建立延迟。潜伏期的重新激活间歇性地发生，这是一个终生的过程 复发性病变的来源。尽管病毒在粘膜中复制或渗透到 神经系统损伤或炎症，发病机制较少 清除。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 哺乳动物细胞中的表达和自噬。值得注意的是，虽然干扰素 刺激基因 (STING) 驱动细胞因子反应三联基序蛋白 23 (TRIM23) 用于介导自噬。尽管有这样的监管控制，HSV 仍能够 损害宿主限制，这取决于 HSV 毒力因子 γ134.5。一个 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 传播、毒力和炎症。目前的努力方向是破译机制 HSV发病机制。 HSV 感染的几个方面将在多方面进行调查 多方面的方法。因此，将产生重组HSV以确定 HSV 与上皮和神经元先天免疫因子相互作用的性质 细胞。这将剖析与核酸传感的病毒干扰相关的元素 复合物和自噬机制。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。与此同时，基因 表达分析将评估眼部和神经炎症。总的来说，这些 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。