Henipavirus Entry and Virion Assembly

描述（由申请方提供）：副粘病毒作为一个组，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、新发人畜共患亨德拉病毒（HeV）和尼帕病毒（NiV）。HeV和NiV具有独特的广泛宿主向性，感染动物和人类，在6个哺乳动物目的至少12个物种中引起全身性且通常致命的呼吸和/或神经疾病。两者都对人类和经济上重要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进入的膜糖蛋白，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，其促进病毒体和宿主细胞膜之间的融合。G和F糖蛋白也是感染宿主中病毒中和抗体应答的主要抗原，并且是旨在阻断病毒进入的几种抗病毒策略的靶标。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具有在没有其他病毒蛋白的情况下从细胞组装和出芽的独特能力。虽然广泛探索，受体结合和融合触发步骤和后代病毒体的组装和出芽的许多细节仍然不明确的亨尼帕病毒和副粘病毒一般。病毒从宿主细胞的进入和退出都是影响宿主嗜性的关键过程，并且亨尼帕病毒是探索关于副粘病毒和负链包膜RNA病毒的这些方面的未回答的问题的新病毒学系统。对亨尼帕病毒的研究将进一步详细了解它们的细胞生物学和参与病毒进入和排出的宿主细胞相互作用。这些工作的结果将有助于深入了解促进有效跨物种传播的机制，并使其成为重要的病原体，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时开发的广泛数据和系统，我们继续我们计划的目标将是进一步详细说明融合和进入过程的各个阶段 以及病毒粒子的组装和出芽。具体而言，我们将：1）表征宿主细胞中的亨尼帕病毒基质驱动的颗粒组装，包括来自其蝙蝠宿主的那些; 2）鉴定和表征参与亨尼帕病毒F和G糖蛋白之间的相互作用和融合触发机制的结构域; 3）定义和详述宿主细胞肝配蛋白受体和亨尼帕病毒G糖蛋白之间的相互作用。

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.