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）是传染失明的最常见原因西方国家的病毒脑炎。原发性或复发性感染可能导致严重的疾病，但没有持牌疫苗。 HSV通常引起感染粘膜的上皮细胞并扩散到病毒的感觉神经元建立延迟。潜伏期的重新激活发生间歇性发生，这是一生复发性病变的来源。虽然在粘膜中复制或渗透到神经系统造成损害或感染，疾病机制较少清除。作为大型DNA病毒，HSV通过先天免疫唤起抗病毒反应调节储罐结合激酶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，干扰素 - 刺激基因（STING）驱动细胞因子反应三方基序蛋白23 （TRIM23）用于介导自噬。尽管进行了这样的监管控制，HSV还是能够妥协宿主限制，取决于HSV病毒因子γ134.5。一个该提议的中心假设是HSV对宿主免疫的重新编程不同，病毒和细胞因子之间的动态相互作用可能决定HSV 扩散，病毒和炎症。当前的努力针对破译机构 HSV发病机理。 HSV感染的几个方面将在多个方面的方法。根据重组HSV的说法，将生成 HSV与上皮和神经元中先天免疫因子相互作用的性质细胞。这将剖析与核酸传感器的病毒干扰有关的元素复合物和自噬机。此外，遗传研究将探索病毒与眼部复制，扩散和神经病毒有关的特征。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病毒遗传决定因素的见解，这可能告知新型抗病毒疗法或阴道的设计。