Viral manipulation of DBC1: a novel strategy to promote cell survival and suppress inflammation

DBC1 的病毒操作：促进细胞存活和抑制炎症的新策略

基本信息

批准号：
BB/T006501/1
负责人：
Carlos Maluquer De Motes
金额：
$ 54.01万
依托单位：
University of Surrey
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FT006501%2F1
关键词：
Viral manipulation DBC1 novel strategy

项目摘要

Human and animal cells have very sophisticated networks to communicate and respond to stress. Infection by a virus is a stress that can lead to the death of the cell. Accordingly cells respond vigorously to viral infection with the aim of blocking viral multiplication and alerting the body's immune system to the ongoing infection. Only viruses that have the capacity to avoid this hostile cell response survive. How viruses achieve this is not always clear. However, if and when one of these viral strategies is discovered, an opportunity for the development of antiviral interventions emerges. This project concerns the discovery of one of those strategies employed by a group of viruses named poxviruses, a member of which was responsible for the devastating disease smallpox. The smallpox virus killed more people in recorded history than all other infectious diseases combined, but fortunately was eradicated thanks to a worldwide vaccination campaign that used vaccinia virus (VACV), another member of the poxvirus family. VACV is currently being studied as a vaccine against another smallpox-like disease known as monkeypox as well as other several important human and animal diseases such as tuberculosis, AIDS, or rabies. This project will study how poxviruses manipulate the activity of a cellular protein termed DBC1. DBC1 belongs to one of those communication networks that cells use to respond to external stress. Its main role is to block the action of another protein known as SIRT1. Both DBC1 and SIRT1 were only discovered ~10 years ago, so our understanding of how they work is still in its infancy. However, it is now clear that both DBC1 and SIRT1 are very important in the process of ageing and in age-related diseases such as cancer and chronic inflammation. This project demonstrates that poxviruses specifically bind and relocalise DBC1, the negative regulator of SIRT1, in a part of the cell where SIRT1 is not normally present. This suggests that poxviruses break the DBC1-SIRT1 connection and benefit from this in a number of ways that are not fully understood yet. This project will therefore determine 1) how poxviruses sequester DBC1 away from SIRT1, 2) what advantage this has for the virus, and 3) what consequences this viral action has in disease and vaccination. To address how, detailed molecular biology and protein localisation studies will be developed. To address why, we will conduct a series of functional tests in cells previously modified to lack DBC1, SIRT1 or both genes. The response of these cells to infection will be studied and compared to that of normal cells. The conclusions from these studies will establish for the first time the role of the DBC1-SIRT1 axis during infection with viruses, and will provide valuable information not only for emerging poxviruses such as the monkeypox virus, but perhaps also for other viruses with similar biology such the African Swine Fever virus - an emerging, economically important pig pathogen that might also sequester DBC1.Finally, given the importance of VACV as a vaccine, the project will study the impact of the DBC1-SIRT1 axis in vaccination using viruses modified in the laboratory to relocate DBC1 or not. The response to vaccination is known to be complex and to change with age. If the modified virus that does not break the DBC1-SIRT1 connection triggers a better immune response, this modification can be introduced into VACV-based vaccines that are currently being developed. Therefore this project has the potential to impact on the design of vaccines and to improve our understanding of ageing and its biology.

人类和动物细胞具有非常复杂的网络，可以沟通和应对压力。病毒感染是一种可能导致细胞死亡的压力。因此，细胞对病毒感染有剧烈反应，目的是阻止病毒繁殖并提醒人体的免疫系统对持续的感染。只有具有避免这种敌对细胞反应的能力的病毒才能存活。病毒如何实现这一目标并不总是很清楚。但是，如果发现这些病毒策略之一，则出现了抗病毒干预措施的机会。该项目涉及发现一组名为Poxviruses的病毒采用的策略之一，其中一组是造成毁灭性疾病天花的成员。天花病毒在记录的历史上杀死了比所有其他传染病的杀害人数更多的人，但幸运的是，由于全球疫苗接种运动使用了poxvirus家族的另一位成员，因此被消除了。 VACV目前正在作为一种针对另一种类似天花的疾病的疫苗，以及其他几种重要的人类和动物疾病，例如结核病，艾滋病或狂犬病。该项目将研究如何操纵称为DBC1的细胞蛋白的活性。 DBC1属于细胞用来响应外部压力的那些通信网络之一。它的主要作用是阻止另一种称为SIRT1的蛋白质的作用。 DBC1和SIRT1都仅在10年前发现，因此我们对它们的工作方式仍处于起步阶段。但是，现在很明显，DBC1和SIRT1在衰老过程和与年龄有关的疾病（例如癌症和慢性炎症）中都非常重要。该项目表明，在通常不存在SIRT1的一部分中，Poxvirues是SIRT1的负调节器的特异性结合和重新定位DBC1。这表明痘病毒打破了DBC1-SIRT1连接，并以多种尚未完全理解的方式从中受益。因此，该项目将确定1）痘病毒如何隔离DBC1远离SIRT1，2）这对病毒具有什么优势，以及3）这种病毒作用在疾病和疫苗接种中产生了什么影响。为了解决如何开发详细的分子生物学和蛋白质定位研究。为了解决原因，我们将在先前修改以缺乏DBC1，SIRT1或两个基因的细胞中进行一系列功能测试。这些细胞对感染的反应将研究并与正常细胞的反应进行比较。这些研究的结论将首次建立DBC1 -SIRT1轴在感染病毒期间的作用，并且不仅将为诸如Monkeypox病毒等新兴的痘病毒提供有价值的信息，也可能为其他类似生物学的病毒，而且对非洲发烧病毒的其他类似的生物学也可能提供了经济上重要的cigation fachention facter andersefental a factiment a factiment a factiment a ventally dbc。疫苗，该项目将使用在实验室中修改的病毒来研究DBC1-SIRT1轴对疫苗接种的影响，以重新定位DBC1。已知对疫苗接种的反应是复杂的，并且随着年龄的增长而变化。如果未破坏DBC1-SIRT1连接的改良病毒会触发更好的免疫反应，则可以将这种修饰引入目前正在开发的基于VACV的疫苗中。因此，该项目有可能影响疫苗设计并提高我们对衰老及其生物学的理解。