Viral determinants in HSV virulence

HSV 毒力的病毒决定因素

• 批准号: 10045324
• 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/10045324
• 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; Encephalitis; Epithelial; Epithelial Cells; Epithelium; Estrogen receptor positive; Event; Excision; Gene Expression; Gene Expression Profiling; Genes; Genetic Determinism; Genetic study; Golgi Apparatus; Growth; 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; 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）是最常见的传染性失明的原因 和病毒性脑炎。原发性或复发性感染可导致 严重的疾病，但没有获得许可的疫苗。HSV通常在以下情况下启动感染： 粘膜上皮细胞并扩散到感觉神经元， 建立延迟。从延迟中重新激活是间歇性的，这是一个终身的过程。 复发病灶的来源。虽然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 清楚作为一种大的DNA病毒，HSV通过先天免疫系统引起抗病毒反应。 调节TANK结合激酶1（激活细胞因子所需的关键因子）的途径 在哺乳动物细胞中表达和自噬。值得注意的是，虽然干扰素- 刺激基因（STING）驱动细胞因子应答，三部分基序蛋白23 （TRIM 23）用于介导自噬。尽管有这样的监管控制，HSV能够 危害宿主限制，这取决于HSV毒力因子γ134.5。一 该建议的中心假设是HSV有区别地重编程宿主免疫， 病毒和细胞因子之间的动态相互作用可能决定HSV 传播、毒性和炎症。目前的努力是针对破译机制， HSV发病机制。HSV感染的几个方面将在一个多- 多层面的方法。因此，将产生重组HSV以确定免疫原性。 单纯疱疹病毒与上皮和神经细胞中先天免疫因子相互作用的性质 细胞这将剖析与核酸感测的病毒干扰有关的元件 复合物和自噬机制。此外，基因研究将探索病毒 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 研究将提供对HSV毒力遗传决定因素的深入了解， 为新型抗病毒治疗剂或疫苗设计提供信息。