Modification of the host lipidome by Rhinovirus infection

小核糖核酸病毒是一类小病毒，是动物和人类的重要病原体。该家族的成员包括脊髓灰质炎病毒、口蹄疫病毒、甲型肝炎病毒和普通感冒病毒（鼻病毒）。鼻病毒（RV）感染是困扰人类的最常见的感染，目前还没有有效的治疗方法或疫苗。虽然普通感冒的症状在健康个体中通常是温和的，但普通感冒仍然是社会的巨大负担。在患有哮喘或慢性阻塞性肺疾病（COPD）的患者中，RV感染可引起其疾病的急性恶化。这是导致严重疾病和死亡的主要原因，并意味着巨大的医疗保健费用。病毒需要劫持宿主细胞的生物系统才能复制。RV像所有的小核糖核酸病毒一样非常简单，但尽管经过多年的研究，人们仍然对它们如何与宿主细胞的生物系统相互作用以复制自己或如何绕过宿主的防御机制知之甚少。在病毒进入宿主细胞后，病毒基因组被翻译成单个长蛋白，随后被切割成参与病毒复制的4种结构外壳蛋白和7种非结构蛋白。这7种非结构蛋白执行复制病毒基因组和在宿主细胞内组装新病毒颗粒所需的功能。为了执行这些功能，病毒蛋白与宿主细胞中的蛋白质和生物系统相互作用，将细胞变成生产病毒的工厂。如果我们要发现阻断病毒的药物，了解这7种病毒蛋白如何将宿主细胞变成病毒生产工厂至关重要。从历史上看，我们曾试图制造针对病毒的抗病毒药物，但病毒非常善于变异，以逃避针对病毒本身的药物的影响。然而，病毒劫持的一些宿主蛋白质本身可能是药物靶点。其优点是，病毒可能不容易突变，以避免针对宿主蛋白质的药物的影响。这个项目的目的是找到我们可以用来制造抗病毒药物的宿主靶点，为此我们必须首先确定病毒是如何在细胞膜上复制的。这些膜是由脂质（或脂肪）和蛋白质组成的，我们相信病毒为了复制而改变了这些膜的脂质和蛋白质组成。在实验中，我们将用病毒感染培养的人肺细胞，然后从感染的细胞中提取脂肪，并使用最先进的生物化学方法测量脂肪含量的任何变化。使用计算技术，我们预计，这些结果将告诉我们的主机系统病毒复制所必需的。我们可以通过敲除这些宿主系统或使用化学抑制剂来阻断它们并测量对病毒复制的影响来证实这些结果。由于我们是在医院环境中工作，我们将来将有能力看到哮喘或COPD患者的这些生物系统是否受到干扰，因此将我们的发现从实验室转化到床边。如果结果看起来很有希望，我们将根据我们的发现启动药物发现计划，无论是我们自己还是与行业合作。该项目是帝国理工学院和Babraham研究所之间的合作伙伴关系，将在两个卓越中心创建一个多学科团队，解决具有重大医学意义的具有挑战性的生物学问题。

Picornaviruses are a family of small viruses that are important pathogens in animals and man. Members of the family include polioviruses, foot and mouth disease virus, hepatitis A virus and the common cold viruses (rhinoviruses). Rhinovirus (RV) infections are the most common infection afflicting mankind and there are no effective therapies or vaccines. Although the symptoms of the common cold are usually mild in healthy individuals, common colds are still an enormous burden to society. In patients with asthma or Chronic Obstructive Pulmonary Disease (COPD) RV infections can provoke acute worsening of their disease. This is a major cause of serious illness and death and represents an enormous health care cost. Viruses need to hijack the host cell's biological systems in order to replicate. RV like all picornaviruses are very simple but despite years of study there is still relatively little known about how they interact with the host cell's biological systems in order to replicate themselves, or how they get around the host's defence mechanisms. Following entry of the virus into a host cell, the viral genome is translated into a single long protein that subsequently gets cut into the 4 structural coat proteins and 7 non-structural proteins that participate in viral replication. These 7 non-structural proteins perform the functions required to replicate the viral genome and to assemble new virus particles inside the host cell. In order to perform these functions, the viral proteins interact with proteins and biological systems in the host cell to turn the cell into a factory for producing virus. Understanding how these 7 viral proteins turn the host cell into a virus producing factory is crucial if we are to discover drugs that block the virus. Historically we have tried to make antiviral drugs that target the virus, but viruses are very good at mutating to escape the effects of drugs targeted at the virus itself. However some of the host proteins that the virus hijacks may be drug targets themselves. The advantage being that the virus may not easily be able to mutate to avoid the effects of drugs targeted at a host protein. The aim of the project is to find host targets to which we can make antiviral drugs.To do this we must first define how the virus replicates on membranes inside the cell. These membranes are made of lipids (or fats) and proteins and we believe the virus changes the lipid and protein composition of these membranes for its replication. Experimentally we will infect cultured human lung cells with the virus and then extract fats from the infected cells and measure any changes in fat content using state of the art biochemistry methods. Using computational techniques we anticipate that these results will tell us about host systems essential for viral replication. We can confirm these results by knocking out these host systems or using chemical inhibitors to block them and measuring the effect on viral replication. As we are working in a hospital setting we will have the ability in future to see if these biological systems are disturbed in patients with asthma or COPD, so translating our findings from the lab to the bedside. If the results look promising, we will start drug discovery programmes based on our findings, either ourselves or by partnering with Industry. The project is a partnership between Imperial College and the Babraham Institute and will create a multi-disciplinary team across two centres of excellence tackling a challenging biological problem of major medical importance.