Glycoprotein interactions in paramyxovirus fusion

副粘病毒融合中的糖蛋白相互作用

• 批准号: 7201879
• 负责人: RONALD M IORIO
• 金额: $ 26.65万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7201879
• 关键词: Accounting; Address; Avidity; Biological Assay; Bronchitis; Canine Distemper Virus; Cell surface; Cells; Central Nervous System Diseases; Child; Chimeric Proteins; Competence; Complex; Croup; Developed Countries; Genes; Giant Cells; Glycoproteins; Goals; HN Protein; Human; Infant; Infection; Kinetics; Link; Measles; Measles virus; Mediating; Membrane Fusion; Membrane Glycoproteins; Modeling; Molecular; Mumps; Mumps virus; Mutation; Newcastle disease virus; Nipah Virus; Oncolytic; Para-Influenza Virus Type 1; Paramyxoviridae; Paramyxovirus; Play; Pneumonia; Process; Proteins; Qualifying; RNA Viruses; Range; Rate; Research; Research Personnel; Respiratory syncytial virus; Role; Sendai virus; Sialic Acids; Simian virus 5; Structure; System; Technology; Temperature; Testing; Time; Vaccination; Viral; Virus; base; dimer; experience; expression vector; glycoprotein structure; influenzavirus; inhibitor/antagonist; killings; mutant; neoplastic cell; parainfluenza virus; pathogen; positional cloning; prevent; programs; receptor; receptor binding; respiratory; small molecule; vector vaccine

DESCRIPTION (provided by applicant): The Paramyxoviridae are enveloped, negative-stranded RNA viruses, including measles virus, human parainfluenza virus (hPIV) types 1-4, respiratory syncytial virus, mumps virus, Newcastle disease virus (NDV), Sendai virus, simian parainfluenza virus 5, and the newly-emerged hendra and nipah viruses. Measles remains a major killer of children worldwide, despite successful vaccination programs in industrialized countries and along with mumps and nipah viruses, causes severe CNS disease. HPIV types 1-3 have long been recognized as causative agents of croup and as important respiratory pathogens, especially of infants and children and hPIVS is a major cause of pneumonia and bronchitis. Recently, NDV has gained importance for its ability to selectively kill tumor cells and has potential for use as both an oncolytic agent and a vaccine vector for expression of foreign genes from other viruses, including influenza virus. The long-term objective of this project is the characterization of the structure/function of the paramyxovirus glycoproteins and their early interactions with the target cell. One of the hallmark cytopathic effects of cells infected with paramyxoviruses is the formation of multi-nucleate syncytia. This process is mediated by membrane fusion induced by a virus-specific interaction between the two viral surface glycoproteins, the attachment (HN/H) and the fusion (F) proteins. The objective of this proposal is to understand the mechanism by which the virus-specific interaction between paramyxovirus glycoproteins regulates the activation of the fusion protein at the proper time and place. A clear understanding of this process will guide anti-viral strategies, such as small molecule inhibitors, aimed at controlling these viruses through interference with the early steps in infection. The specific aims of this proposal are to elucidate the molecular basis for the correlation between the strength of the HN-receptor interaction and the level of membrane fusion, to follow the status of the glycoprotein complex through the fusion process, to test various models proposed for the mechanism of HN-F mediated fusion and, to demonstrate the complementarity of the interacting domains on the NDV HN and F proteins.

描述（申请人提供）：副粘病毒科是有包膜、负链RNA病毒，包括麻疹病毒、人副流感病毒（hPIV）1-4型、呼吸道合胞病毒、腮腺炎病毒、新城疫病毒（NDV）、仙台病毒、猿猴副流感病毒5型以及新出现的亨德拉病毒和尼帕病毒 病毒。尽管工业化国家的疫苗接种计划取得了成功，麻疹仍然是全世界儿童的主要杀手，并且与流行性腮腺炎和尼帕病毒一起引起严重的中枢神经系统疾病。长期以来，1-3 型 HPIV 一直被认为是哮吼的病原体和重要的呼吸道病原体，尤其是婴儿和儿童，并且 hPIVS 是肺炎和支气管炎的主要原因。最近，NDV 因其选择性杀死肿瘤细胞的能力而变得重要，并且有潜力用作溶瘤剂和表达其他病毒（包括流感病毒）外源基因的疫苗载体。该项目的长期目标是表征副粘病毒糖蛋白的结构/功能及其与靶细胞的早期相互作用。副粘病毒感染细胞的标志性细胞病变效应之一是多核合胞体的形成。该过程是由两种病毒表面糖蛋白、附着蛋白（HN/H）和融合蛋白（F）之间的病毒特异性相互作用诱导的膜融合介导的。该提案的目的是了解副粘病毒糖蛋白之间的病毒特异性相互作用在适当的时间和地点调节融合蛋白的激活的机制。清楚地了解这一过程将指导抗病毒策略，例如小分子抑制剂，旨在通过干扰感染的早期步骤来控制这些病毒。本提案的具体目的是阐明 HN-受体相互作用强度与膜融合水平之间相关性的分子基础，通过融合过程跟踪糖蛋白复合物的状态，测试为 HN-F 介导融合机制提出的各种模型，并证明 NDV HN 和 F 蛋白上相互作用域的互补性。