Glycoprotein interactions in paramyxovirus fusion

描述（由申请人提供）：副粘病毒科是包膜的负链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、类人猿副流感病毒5型以及新出现的亨德拉病毒和尼帕病毒。尽管工业化国家成功实施了疫苗接种计划，但麻疹仍然是全球儿童的主要杀手，它与腮腺炎和尼帕病毒一起导致严重的中枢神经系统疾病。HPIV 1-3型长期以来被认为是群体的病原体，是重要的呼吸道病原体，特别是婴儿和儿童，HPIV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受到重视，并且有可能作为溶瘤剂和用于表达来自其他病毒（包括流感病毒）的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。副粘病毒感染的细胞病变的标志之一是形成多核合胞体。这一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。本研究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激活的机制。对这一过程的清晰理解将指导抗病毒策略，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。本课题的具体目的是阐明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，检验提出的HN-F介导融合机制的各种模型，并证明NDV HN和F蛋白上相互作用结构域的互补性。

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.