Innate immune restriction of enveloped virus exit

感染呼吸道的病毒每年造成全球大量死亡，特别是在营养不良者、儿童和老年人等弱势群体中。最重要的两种呼吸道病毒是呼吸道合胞病毒（RSV）和麻疹病毒（MeV）。目前还没有针对呼吸道合胞病毒的疫苗，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15万儿童死于这种疾病，主要是因为这种病毒引起肺炎和其他严重的呼吸道感染。MeV的情况更为复杂，因为尽管我们有疫苗，但尚未用于完全根除该病毒。因此，由于MeV本身具有极强的传染性，每年仍有大约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研究的重要病毒。如果我们能提高对这些病毒的了解，我们就能设计出更好的药物和疫苗来对付这些感染，减少它们给全球医疗保健带来的压力。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，当这些病毒在人体气道中建立自己的时候。本项目旨在回答与医学和科学相关的问题，如：1。细胞是如何对抗RSV和MeV感染的，特别是这些病原体在何时何地受到限制？这些病毒感染如何以及为什么会导致疾病？为什么有些人比其他人更容易感染这些感染？免疫反应本身是否有时会引起问题？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组成的网络，它们已经进化到可以检测病原体，如病毒，并抑制它们的复制和持续传播。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，我们将进行的实验是：RSV和MeV在一个称为出芽的过程中从受感染的细胞窃取它们的包膜或外壳。这一过程依赖于许多病毒蛋白，它们共同作用产生感染性颗粒。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各个阶段。通过这些试验，我将检验来自先天免疫系统的单个蛋白质是否能抑制新病毒颗粒的形成。另外，我已经开发了新的技术，可以纯化RSV和MeV复制的细胞膜。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了这个部分。然后，我将对鉴定出的蛋白质进行表征，以研究它们是如何、在何处以及何时抑制这些感染的。此外，我将研究它们在呼吸道模型中的相关性，并研究这些蛋白质的遗传变异是否会影响它们的功能。总结;该项目将检查和描述对RSV和MeV这两种重要的儿童呼吸道疾病的免疫反应。

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.