Henipavirus Entry and Virion Assembly

描述(申请人提供)：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，以及高致病性、新出现的人畜共患病病毒：亨德拉病毒(HEV)和尼帕病毒(NIV)。HEV和NIV具有独特的广泛宿主嗜性，感染动物和人类，在6目哺乳动物的至少12个物种中引起一种系统性的、往往是致命的呼吸道和/或神经系统疾病。这两种生物对人类和经济上重要的牲畜都构成了重要的生物安全。海尼帕病毒具有两种参与病毒侵入的膜糖蛋白，一种是介导宿主细胞受体结合的糖蛋白(G糖蛋白)，另一种是促进病毒粒子与宿主细胞膜融合的第I类融合(F)糖蛋白。G和F糖蛋白也是受感染宿主中和病毒抗体反应的主要抗原，也是几种旨在阻止病毒进入的抗病毒策略的靶标。相反，基质(M)蛋白是病毒粒子的重要结构成分，已被证明在后代病毒的形态发生和萌发过程中发挥核心作用。汉尼帕病毒M具有一种独特的能力，可以在没有其他病毒蛋白的情况下从细胞中组装和发芽。尽管进行了广泛的研究，但对于海尼帕病毒和副粘病毒来说，受体结合和融合触发步骤以及子代病毒粒子的组装和萌发的许多细节仍然没有明确的定义。病毒进入和离开宿主细胞都是影响宿主嗜性的关键过程，而海尼帕病毒是一个新的病毒学系统，在这个系统中探索副粘病毒和负链包膜RNA病毒的这些方面的未解问题。对埃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出的宿主细胞相互作用。这些努力的发现将提供对促进有效跨物种传播的机制的洞察，并使其成为重要的病原体，并将有助于开发新的抗病毒战略。我们的工作主要集中在海尼帕病毒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萌发。利用我们在研究HEV和NIV时开发的大量数据和系统，以及一种新的埃尼帕病毒物种，我们在继续我们的计划时的目标是进一步详细说明融合和进入过程的各个阶段。 以及病毒颗粒的组装和萌芽。具体地说，我们将：1)表征病毒基质驱动的颗粒在宿主细胞中的组装，包括来自其BAT宿主的颗粒组装；2)鉴定和表征参与鸡痘病毒F和G糖蛋白之间相互作用和融合触发机制的结构域；3)定义和详细描述宿主细胞ePhin受体和河豚病毒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.