Glycoprotein interactions in paramyxovirus fusion

副粘病毒科是有包膜的负链RNA病毒，包括麻疹病毒、人类 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 新城疫病毒(NDV)、仙台病毒、猴副流感病毒5，以及新出现的亨德拉和尼帕病毒。 麻疹仍然是全球儿童的主要杀手，尽管疫苗接种计划在 工业化国家和地区与流行性腮腺炎和尼帕病毒一起，导致严重的CMS病。HPIV类型 1-3长期以来一直被认为是引起哮喘的病原体和重要的呼吸道病原体， 尤其是婴儿和儿童，hPIVS是肺炎和支气管炎的主要原因。最近，新城疫病毒 因其选择性杀伤肿瘤细胞的能力而变得重要，并有可能用作 用于表达包括流感在内的其他病毒的外源基因的溶瘤剂和疫苗载体 病毒。这一项目的长期目标是描述 副粘病毒糖蛋白及其与靶细胞的早期相互作用。一种标志性的细胞病变 细胞感染副粘病毒的影响是形成多核合胞体。这个过程是 由病毒特异性相互作用诱导的膜融合介导的病毒表面 糖蛋白、附着蛋白(HN/H)和融合蛋白(F)。这项建议的目的是 了解副粘病毒糖蛋白与病毒特异性相互作用的机制 在适当的时间和地点调节融合蛋白的激活。对此有一个清醒的认识 该过程将指导旨在控制这些病毒的抗病毒策略，如小分子抑制剂 通过干预感染的早期步骤。这项建议的具体目的是澄清 HN-受体相互作用强度与血管紧张素转换酶水平相关性的分子基础 膜融合，以跟踪糖蛋白复合体的状态通过融合过程，以检测各种 提出了HN-F介导的融合机制模型，并证明了HN-F介导的融合的互补性 新城疫病毒HN和F蛋白的相互作用结构域。

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 CMSdisease. 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.