Innate immune restriction of enveloped virus exit

有包膜病毒退出的先天免疫限制

• 批准号: MR/P021735/1
• 负责人: Dalan Bailey
• 金额: $ 56.97万
• 依托单位: The Pirbright Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP021735%2F1
• 关键词: Innate; immune; restriction; enveloped; virus

Viruses that infect the respiratory tract are responsible for a huge number of global deaths every year, especially in vulnerable populations like the malnourished, children and the elderly. Two of the most significant respiratory viruses are RSV (respiratory syncytial virus) and MeV (measles virus). There is no vaccine to RSV and most children will have had this infection by the time they are 2 years old. Unfortunately, around 150,000 children a year die from this disease, mostly because the virus causes pneumonia and other serious infections of the airways. The situation with MeV is more complex because although we have a vaccine it has not been used to fully eradicate the virus. As a result, and because MeV itself is incredibly infectious, around 115,000 people still die from this infection every year. RSV and MeV are therefore important viruses to study in the laboratory and hospital setting. If we can improve our understanding of these viruses we can design better drugs and vaccines to tackle these infections, reducing the strain they place on global healthcare.My research is focused on the immune response to RSV and MeV, especially during the early stages of disease when these viruses are establishing themselves in the human airway. This project is designed to answer medically and scientifically relevant questions such as:1. How does the cell work to fight RSV and MeV infection, in particular when and where are these pathogens targeted for restriction?2. How and why do these viral infections cause disease?3. Why some people are more susceptible than others to these infections?4. Whether the immune response itself can sometimes cause problems?My project will focus on the early acting innate immune system. This is made up of a network of sensors and effectors that have evolved to detect pathogens, like viruses, and inhibit their replication and continued spread. I will examine how RSV and MeV are inhibited by this pathway, focusing on the formation and release of virus particles. This is an important stage in the viral life cycle because it is essential for continued infection. As such, improving our knowledge of this process could lead to the development of targeted antivirals. To be more specific about the experiments we will perform: RSV and MeV steal their envelope, or coat, from the infected cell during a process called budding. This process is reliant on a number of viral proteins that work together to make infectious particles. I have developed high-throughput assays that let me investigate these proteins and the various stages of the viral life-cycle in greater detail. Using these assays I will examine whether individual proteins from the innate immune system can inhibit the formation of new virus particles. Separately I have developed new techniques that allow purification of the cellular membranes where RSV and MeV replicate. I will use this technology to examine what immune proteins are drawn into this fraction during infection. The proteins that I identify will then be characterised to examine how, where and when they work to inhibit these infections. In addition I will investigate their relevance in models of the respiratory tract and also examine whether genetic variation in these proteins affects their function. To summarise; this project will examine and characterise the immune response to RSV and MeV, two important childhood disease of the respiratory tract.

感染呼吸道的病毒每年导致全球大量死亡，特别是在营养不良者、儿童和老年人等脆弱人群中。两种最重要的呼吸道病毒是RSV(呼吸道合胞病毒)和MeV(麻疹病毒)。目前还没有针对RSV的疫苗，大多数儿童在2岁时就会感染这种病毒。不幸的是，每年约有15万名儿童死于这种疾病，主要是因为这种病毒导致肺炎和其他严重的呼吸道感染。MeV的情况更复杂，因为尽管我们有疫苗，但它还没有被用来完全根除病毒。因此，由于MeV本身具有令人难以置信的传染性，每年仍有约11.5万人死于这种感染。因此，RSV和MeV是实验室和医院环境中需要研究的重要病毒。如果我们能够提高对这些病毒的理解，我们就可以设计出更好的药物和疫苗来应对这些感染，减少它们给全球卫生保健带来的压力。我的研究重点是对RSV和MeV的免疫反应，特别是在疾病的早期阶段，当这些病毒进入人类呼吸道时。这个项目旨在回答与医学和科学相关的问题，例如：1.细胞如何工作来对抗RSV和MeV感染，特别是这些病原体何时何地被限制？2.这些病毒感染是如何以及为什么导致疾病的？3.为什么有些人比其他人更容易感染这些感染？4.免疫反应本身有时是否会造成问题？我的项目将专注于早期作用的先天免疫系统。这是由传感器和效应器网络组成的，这些传感器和效应器已经进化到检测病原体，如病毒，并抑制它们的复制和继续传播。我将研究RSV和MeV是如何被这一途径抑制的，重点是病毒颗粒的形成和释放。这是病毒生命周期中的一个重要阶段，因为它对持续感染至关重要。因此，提高我们对这一过程的了解可能会导致靶向抗病毒药物的开发。更具体地说，我们将进行的实验：RSV和MeV在一个称为发芽的过程中从受感染的细胞中窃取它们的包膜或皮毛。这一过程依赖于大量的病毒蛋白，这些蛋白共同作用形成具有感染性的颗粒。我已经开发出高通量分析方法，使我能够更详细地研究这些蛋白质和病毒生命周期的不同阶段。利用这些分析，我将检验来自先天免疫系统的单个蛋白质是否能够抑制新病毒颗粒的形成。另外，我开发了一种新技术，可以对RSV和MeV复制的细胞膜进行纯化。我将使用这项技术来检查在感染过程中哪些免疫蛋白被吸入这一部分。然后，我确定的蛋白质将进行特征描述，以检查它们如何、在哪里以及何时抑制这些感染。此外，我还将研究它们在呼吸道模型中的相关性，并检查这些蛋白质的遗传变异是否会影响它们的功能。总而言之，这个项目将检查和描述对RSV和MeV的免疫反应，这是两种重要的儿童呼吸道疾病。

项目成果

Respiratory syncytial virus sequesters NF-?B subunit p65 to cytoplasmic inclusion bodies to inhibit innate immune signalling

呼吸道合胞病毒将 NF-κB 亚基 p65 隔离到细胞质包涵体中以抑制先天免疫信号传导

• DOI: 10.1101/2020.02.11.944363
• 发表时间: 2020
• 作者: Jobe F

Bacterial flagellin promotes viral entry via an NF-kB and Toll Like Receptor 5 dependent pathway

• DOI: 10.1038/s41598-019-44263-7
• 发表时间: 2019-05-27
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Benedikz, Elizabeth K.;Bailey, Dalan;McKeating, Jane A.
• 通讯作者: McKeating, Jane A.

Structure-Guided Identification of a Nonhuman Morbillivirus with Zoonotic Potential.

• DOI: 10.1128/jvi.01248-18
• 发表时间: 2018-12-01
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Abdullah N;Kelly JT;Graham SC;Birch J;Gonçalves-Carneiro D;Mitchell T;Thompson RN;Lythgoe KA;Logan N;Hosie MJ;Bavro VN;Willett BJ;Heaton MP;Bailey D
• 通讯作者: Bailey D

Combinatorial F-G Immunogens as Nipah and Respiratory Syncytial Virus Vaccine Candidates.

组合F-G免疫原作为NIPAH和呼吸道合胞病毒疫苗候选。

• DOI: 10.3390/v13101942
• 发表时间: 2021-09-28
• 期刊: Viruses
• 作者: Isaacs A;Cheung STM;Thakur N;Jaberolansar N;Young A;Modhiran N;Bailey D;Graham SP;Young PR;Chappell KJ;Watterson D
• 通讯作者: Watterson D

The SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins.

• DOI: 10.1371/journal.pbio.3001016
• 发表时间: 2020-12
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Conceicao C;Thakur N;Human S;Kelly JT;Logan L;Bialy D;Bhat S;Stevenson-Leggett P;Zagrajek AK;Hollinghurst P;Varga M;Tsirigoti C;Tully M;Chiu C;Moffat K;Silesian AP;Hammond JA;Maier HJ;Bickerton E;Shelton H;Dietrich I;Graham SC;Bailey D
• 通讯作者: Bailey D