Impact of BHV-1 tegument proteins on the innate response to infection and virion morphogenesis.

BHV-1 外皮蛋白对感染和病毒颗粒形态发生的先天反应的影响。

• 批准号: RGPIN-2016-06230
• 负责人: vanDrunenLittelvandenHurk, Sylvia
• 金额: $ 3.21万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=667517
• 关键词: Impact; BHV; tegument; proteins; innate

Bovine herpesvirus-1 (BoHV-1) has a severe impact on growth, milk production, and international livestock trade, thus being responsible for major economic damage to the cattle industry worldwide. In North America BoHV-1 is part of the bovine respiratory disease complex, which costs the cattle industry >1 billion dollars each year. In addition, BoHV-1 is an emerging virus in buffalo. Herpesviruses are composed of four concentric compartments, the nucleoprotein core, capsid, tegument and envelope. Tegument proteins are the first to interact with the intracellular environment and at a later stage associate to create the tegument of new virions. Some herpesvirus tegument proteins have important functions, for instance in regulation of transcription and in virus morphogenesis. The mechanism and site of BoHV-1 tegument formation, and the functions of its protein components are largely unknown.***The overall goal of this program is to perform a functional characterization of the tegument proteins of BoHV-1. The short-term objective is to characterize the role of tegument protein VP8 in the host response to BoHV-1 infection, virus assembly and fitness. Infection of bovine cells or calves with BoHV-1 leads to a strong intrinsic host response. This suggests that the virus needs to counteract this response early during infection. VP8 is the most abundant viral protein, is detected in tissue culture at 2 h post-infection before de novo synthesis and is essential for infection of cattle. We hypothesize and already have evidence that VP8 plays an important role in overcoming early intrinsic defences of the host. We will further elucidate the mechanism and the critical domains of VP8 that are responsible for this phenomenon. Secondly, as the virion morphology and composition is altered in a VP8 deletion mutant virus, we hypothesize VP8 to play a role in virus morphogenesis. To investigate this, we will identify the VP8-protein interaction networks required for tegument formation and assembly of BoHV-1. The long-term objective is to characterize additional BoHV-1 tegument proteins. To obtain a basis for these studies, we will define the composition of BoHV-1 virions at different stages of maturation. This will lead to the identification of additional potentially important tegument proteins, to be further studied in context of BoHV-1 pathogenesis and morphogenesis.***The results of this program are expected to have a significant impact on the rational design of attenuated BoHV-1 vaccines based on deletion or modification of specific virulence factors. Furthermore, therapeutics that target tegument proteins and interrupt initiation of infection or virus assembly may be developed. With the availability of cattle as the natural host for in vivo testing of new vaccines or therapeutics, which will expedite licensing, this work will quickly be of benefit to the livestock industry in Canada and worldwide. *** *** **

牛疱疹病毒-1(BoHV-1)对牛的生长、牛奶生产和国际牲畜贸易造成严重影响，从而对全球养牛业造成重大经济损失。在北美，BoHV-1是牛呼吸道疾病复合体的一部分，每年给养牛业造成10亿美元的损失。此外，BoHV-1是水牛中出现的一种新病毒。疱疹病毒由核蛋白核心、衣壳、被膜和包膜四个同心隔室组成。被膜蛋白首先与细胞内环境相互作用，在后来的阶段形成新的病毒粒子的被层。一些疱疹病毒被膜蛋白具有重要的功能，例如在转录调控和病毒形态发生中。BoHV-1被膜形成的机制和部位及其蛋白质组分的功能在很大程度上尚不清楚。*本计划的总体目标是对BoHV-1被膜蛋白进行功能鉴定。短期目标是表征被膜蛋白VP8在宿主对BoHV-1感染的反应、病毒组装和适合性中的作用。BoHV-1感染牛细胞或小牛可引起强烈的内源性宿主反应。这表明病毒需要在感染早期抵消这种反应。VP8是病毒中含量最丰富的蛋白，在感染后2小时组织培养中可检测到VP8蛋白的从头合成，对牛的感染是必需的。我们假设并已经有证据表明，VP8在克服宿主早期的内在防御方面发挥着重要作用。我们将进一步阐明VP8导致这一现象的机制和关键结构域。其次，由于VP8缺失突变病毒中病毒粒子的形态和组成发生了改变，我们推测VP8在病毒的形态发生中起作用。为了研究这一点，我们将确定BHV-1的被形成和组装所需的VP8-蛋白质相互作用网络。长期目标是鉴定更多的BoHV-1被膜蛋白。为了获得这些研究的基础，我们将定义BoHV-1病毒粒子在不同成熟阶段的组成。这将导致识别其他潜在的重要被膜蛋白，以便在BoHV-1发病机制和形态发生的背景下进一步研究。*该计划的结果有望对基于特定毒力因子缺失或修改的减毒BoHV-1疫苗的合理设计产生重大影响。此外，靶向被膜蛋白并阻断感染或病毒组装的治疗方法也可能被开发出来。随着牛作为新疫苗或疗法体内测试的自然宿主的可用性，这将加快许可速度，这项工作将很快为加拿大和世界各地的畜牧业带来好处。*