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。初次或反复感染可导致 严重的疾病，但还没有获得许可的疫苗。单纯疱疹病毒通常会在 粘膜上皮细胞扩散到感觉神经元，在那里病毒 建立延迟。从延迟中重新激活会间歇性地发生，这是终生的 复发皮损的来源。尽管病毒在粘膜中复制或渗透到 神经系统受损或发炎，发病机制较少 安全。作为一种大型DNA病毒，单纯疱疹病毒通过先天免疫激发抗病毒反应。 调节坦克结合激酶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，当干扰素- 刺激基因(STING)驱动细胞因子对三聚体基序蛋白23的反应 (TRIM23)起到调节自噬的作用。尽管有这样的监管控制，HSV仍然能够 妥协宿主限制，这取决于单纯疱疹病毒毒力因子γ134.5。一个 这一提议的中心假设是单纯疱疹病毒对宿主免疫进行了差异化的重新编程， 其中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。目前的努力是为了破译 单纯疱疹病毒的发病机制。将对HSV感染的几个方面进行多方面的调查。 多方面的方法。相应地，将产生重组HSV来确定 上皮和神经元中单纯疱疹病毒与天然免疫因子相互作用的性质 细胞。这将剖析与核酸感应的病毒干扰有关的元素。 复合体和自噬机器。此外，基因研究将探索病毒 与眼部复制、扩散和神经毒性相关的特征。同时，基因 表达分析将评估眼部和神经细胞炎症。总而言之，这些 研究将提供对HSV毒力的遗传决定因素的洞察，这可能 为新型抗病毒疗法或疫苗的设计提供信息。