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: $ 6.41万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=766054
• 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) 对生长、牛奶生产和国际牲畜贸易产生严重影响，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，每年给养牛业造成超过 10 亿美元的损失。此外，BoHV-1 是水牛中新出现的病毒。疱疹病毒由四个同心区室组成，即核蛋白核心、衣壳、外皮和包膜。外皮蛋白首先与细胞内环境相互作用，并在后期联合形成新病毒粒子的外皮。一些疱疹病毒外皮蛋白具有重要功能，例如在转录调节和病毒形态发生中。 BoHV-1 外皮形成的机制和位点以及其蛋白质成分的功能在很大程度上是未知的。该程序的总体目标是对 BoHV-1 外皮蛋白进行功能表征。短期目标是表征外皮蛋白 VP8 在宿主对 BoHV-1 感染、病毒组装和适应性的反应中的作用。 BoHV-1 感染牛细胞或小牛会导致强烈的内在宿主反应。这表明病毒需要在感染早期抵消这种反应。 VP8 是最丰富的病毒蛋白，在感染后 2 小时从头合成之前的组织培养物中检测到，对于牛的感染至关重要。我们假设并且已经有证据表明 VP8 在克服宿主早期内在防御方面发挥着重要作用。我们将进一步阐明造成这种现象的机制和 VP8 的关键域。其次，由于 VP8 缺失突变病毒的病毒粒子形态和组成发生了改变，我们假设 VP8 在病毒形态发生中发挥作用。为了研究这一点，我们将确定 BoHV-1 被膜形成和组装所需的 VP8-蛋白质相互作用网络。长期目标是表征其他 BoHV-1 被膜蛋白。为了获得这些研究的基础，我们将定义 BoHV-1 病毒体在不同成熟阶段的组成。这将导致鉴定出其他潜在重要的外皮蛋白，并在 BoHV-1 发病机制和形态发生的背景下进一步研究。该计划的结果预计将对基于 BoHV-1 减毒疫苗的合理设计产生重大影响。删除或修改特定毒力因子。此外，可以开发针对被膜蛋白并中断感染或病毒组装起始的治疗方法。随着牛作为新疫苗或疗法体内测试的自然宿主的出现，这将加快许可速度，这项工作将很快使加拿大和全世界的畜牧业受益。