Henipavirus Entry and Virion Assembly

描述（由申请人提供）：副粘病毒作为一个群体，包括许多重要的人类和动物病原体，如麻疹病毒、副流感病毒和高致病性、新出现的人畜共患亨德拉病毒（HeV）和尼帕病毒（NiV）。戊肝病毒和NiV具有独特的广泛宿主嗜性，可感染动物和人类，在6目哺乳动物中至少12种中引起全身性且往往致命的呼吸道和/或神经系统疾病。两者都对人类和具有重要经济意义的牲畜构成重大的生物威胁。亨尼帕病毒具有两种参与病毒侵入的膜糖蛋白，一种介导宿主细胞受体附着（G糖蛋白），另一种是I类融合(F)糖蛋白，促进病毒粒子与宿主细胞膜之间的融合。G和F糖蛋白也是受感染宿主中病毒中和抗体反应的主要抗原，也是几种旨在阻断病毒进入的抗病毒策略的靶点。相反，基质(M)蛋白是病毒粒子的基本结构成分，并已被证明在子代病毒的形态发生和出芽中发挥核心作用。亨尼帕病毒M具有一种独特的能力，在没有其他病毒蛋白的情况下从细胞中组装和发芽。尽管对亨尼帕病毒和副粘病毒进行了广泛的研究，但关于受体结合和融合触发步骤以及子代病毒粒子的组装和出芽的许多细节仍然不清楚。病毒从宿主细胞的进入和退出都是影响宿主趋向性的关键过程，而亨尼帕病毒是一个新的病毒学系统，在这个系统中，人们可以探索副粘病毒和负链包膜RNA病毒在这些方面的未解之谜。对亨尼帕病毒的研究将进一步详细了解其细胞生物学和参与病毒进入和退出的宿主细胞相互作用。这些努力的发现将有助于深入了解促进有效跨物种传播的机制，并使它们成为重要的病原体，并将有助于开发新的抗病毒策略。我们的工作主要集中在亨尼帕病毒F和G糖蛋白，受体结合和融合步骤，以及病毒样颗粒的组装和出芽。利用我们在研究HeV和NiV以及一种新的亨尼帕病毒方面开发的广泛数据和系统，我们的目标将是进一步详细介绍融合和进入过程的各个阶段

DESCRIPTION (provided by applicant): The paramyxoviruses, as a group, include many important human and animal pathogens, such as measles virus, the parainfluenza viruses, and the highly pathogenic, emerging, zoonotic henipaviruses: Hendra virus (HeV) and Nipah virus (NiV). HeV and NiV have a uniquely broad host tropism, infecting both animals and humans, causing a systemic and often fatal respiratory and/or neurological disease in at least 12 species across 6 orders of mammals. Both pose significant biothreats to both humans and economically important livestock. Henipaviruses, possess two membrane glycoproteins involved in virus entry, one mediates host cell receptor attachment (G glycoprotein) and the other is a Class I fusion (F) glycoprotein which facilitates fusion between the virion and host cell membranes. The G and F glycoproteins are also the major antigens of the virus-neutralizing antibody response in infected hosts and the targets of several antiviral strategies aimed at blocking virus entry. Conversely, the matrix (M) protein is an essential structural component of the virion and has been shown to play a central role in the morphogenesis and budding of progeny virus. Henipavirus M possess a unique ability to assemble and bud from cells in the absence of other viral proteins. Although extensively explored, many details of both the receptor binding and fusion triggering steps and the assembly and budding of progeny virions remain ill-defined for the henipaviruses and paramyxoviruses in general. Both the entry and exit of virus from the host cell are critical processes which also influence host tropism, and the henipaviruses are new virological systems in which to explore unanswered questions about these aspects of paramyxoviruses and negative-stranded enveloped RNA viruses in general. Studies on henipaviruses will further a detailed understanding of their cell biology and host cell interaction involved in virus entry and egress. Findings from these efforts will provide insight into the mechanisms that foster efficient cross-species transmission and also make them important pathogens, and will aid in the development of new antiviral strategies. Our efforts have focused on the henipavirus F and G glycoproteins, the receptor-binding and fusion steps, and the assembly and budding of virus-like-particles. Using the extensive data and systems we have developed in studying HeV and NiV, together with a new species of henipavirus, our objectives in the continuation of our program will be to further detail stages in the fusion and entry process and the assembly and budding of virus particles. Specifically, we will: 1) Characterize henipavirus matrix driven particle assembly in host cells including those from their bat hosts; 2) Identify and characterize the domains involved in the interaction and fusion-triggering mechanism between the henipavirus F and G glycoproteins; 3) Define and detail the interactions between the host cell ephrin receptors and henipavirus G glycoproteins.