Alpha-herpevirus assembly egress and viral particle heterogeneity

α-疱疹病毒装配出口和病毒颗粒异质性

• 批准号: 8212020
• 负责人: Gregory Allan Smith
• 金额: $ 30.2万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212020
• 关键词: Acyclovir; Address; Affect; Antiviral Agents; Blindness; Capsid; Capsid Proteins; Cell Nucleus; Cells; Comparative Study; Country; Coupled; Cytoplasm; Developed Countries; Disease; Disease Progression; Encephalitis; Goals; Herpes zoster disease; Herpesviridae; Herpesvirus 1; Herpesvirus Type 3; Heterogeneity; Human; Human Herpesvirus 2; Individual; Infection; Intervention; Keratitis; Life; Link; Measures; Molecular; Morbidity - disease rate; Mutagenesis; Neonatal; Newborn Infant; Nuclear; Nuclear Envelope; Pathway interactions; Process; Property; Proteins; Role; Series; Simplexvirus; Staging; Structure; Study models; Subgroup; Suid Herpesvirus 1; Varicellovirus; Viral; Viral Pathogenesis; Viral Proteins; Virus; Virus Diseases; X-Ray Crystallography; base; domain mapping; fluorescence imaging; imaging modality; member; mortality; mutant; novel strategies; particle; pathogen; public health relevance

DESCRIPTION (provided by applicant): The neuroinvasive herpesviruses are a highly-prevalent group of the alpha-herpesvirus subfamily that includes the human pathogens: herpes simplex virus types 1 and 2 (HSV-1, HSV-2), and varicella zoster virus (VZV). An additional member of this group is a virus of veterinary significance, pseudorabies virus (PRV), which historically has provided models for studying viral pathogenesis. Despite the availability of the antiviral compound acyclovir, several severe forms of disease caused by these viruses remain prevalent in this country and worldwide. Infections associated with high rates of morbidity or mortality includes encephalitis, keratitis, shingles and disseminated infections in newborns. Novel strategies to interfere with the assembly and egress of these viruses could prove valuable to treatment of infections, yet much of the herpesvirus infectious cycle remains undefined. In this application we leverage our expertise in infectious clone mutagenesis and single viral particle fluorescence imaging methods to dissect viral structural composition in living-cells and extracellularly, and to address the molecular pathways guiding viral assembly and egress. New evidence is provided indicating that the very large herpesvirus tegument protein, VP1/2, is a key effector of viral assembly during distinct stages of assembly in the nucleus and cytoplasm of infected cells. This proposal is based on the hypothesis that herpesvirus assembly and egress are coupled processes that occur through a series of sequential steps both in the nucleus and cytoplasm of infected cells, and that each of these steps are affected in part by the VP1/2 protein. Our goal is to refine our understanding of these steps at the level of the protein interactions that contribute to the dynamics of viral egress. This proposal includes comparative studies of model viruses from the two neuroinvasive herpesviruses subgroups, the simplex viruses (represented by HSV-1) and the varicelloviruses (represented by PRV), to develop a comprehensive analysis of the properties of these viruses. PUBLIC HEALTH RELEVANCE: Neuroinvasive herpesviruses are the causative agents of a number of severe diseases including shingles, encephalitis, neonatal infections and herpes keratitis (the leading cause of infectious blindness in the USA and other industrialized nations). This proposal focuses on understanding the molecular mechanisms that underlie the assembly and egress of herpesvirus particles, with the long- term goal of identifying new targets for the intervention of disease progression.

描述（由申请人提供）：神经侵袭性疱疹病毒是包括人病原体在内的α-疱疹病毒亚家族的一组高度可持续的组：单纯疱疹病毒类型1和2（HSV-1，HSV-2）和Varicella Zoster Zoster病毒（VZV）。该组的另一个成员是具有兽医意义的病毒，即伪标记病毒（PRV），该病毒历史上为研究病毒发病机理提供了模型。尽管抗病毒化合物阿西洛韦有可用性，但这些病毒引起的几种严重形式的疾病在这个国家和世界范围内仍然普遍存在。与高发病率或死亡率相关的感染包括新生儿中的脑炎，角膜炎，带状疱疹和传播感染。干扰这些病毒的组装和出口的新型策略可能证明对感染的治疗很有价值，但是许多疱疹病毒感染周期仍然不确定。在此应用中，我们利用我们在传染性克隆诱变和单个病毒颗粒荧光成像方法方面的专业知识来剖析活细胞和细胞外病毒结构组成，并解决指导病毒组装和egress的分子途径。提供了新的证据，表明非常大的疱疹病毒tegument蛋白VP1/2是病毒组装的关键效应因子，在核中不同的组装阶段和受感染细胞的细胞质的不同阶段。该提议基于以下假设：疱疹病毒组装和出口是通过一系列的核和感染细胞细胞质的顺序步骤进行的耦合过程，并且这些步骤中的每个步骤都受VP1/2蛋白的部分影响。我们的目标是在蛋白质相互作用的水平上完善我们对这些步骤的理解，这些蛋白质相互作用有助于病毒出口的动力学。该建议包括对两个神经侵染疱疹病毒亚组的模型病毒的比较研究，单纯形病毒（由HSV-1代表）和Varicelloviruses（由PRV代表），以对这些病毒的性质进行全面分析。 公共卫生相关性：神经侵袭性疱疹病毒是多种严重疾病的病因，包括带状疱疹，脑炎，新生儿感染和疱疹角膜炎（美国和其他工业化国家传染性失明的主要原因）。该提案的重点是理解疱疹病毒颗粒组装和出口的分子机制，其长期目标是确定疾病进展干预的新目标。