Common host proteins required for replication organelle function across coronaviruses

冠状病毒是感染人类和家畜的一组重要病原体。人类冠状病毒主要导致常见的感冒类型疾病，约占因呼吸道感染而住院的10%。此外，2016年估计有3400万个工作日因咳嗽和感冒而损失，这意味着冠状病毒是造成生产力损失的主要原因之一。冠状病毒也是经济上重要的牲畜疾病的原因。英国家禽业每年为经济贡献34亿GB，最具经济破坏性的传染病是由冠状病毒传染性支气管炎病毒引起的，估计每年有2300万GB因此而损失。在猪方面，2013-2014年美国爆发的另一种冠状病毒-猪流行性腹泻病毒估计导致800万头猪死亡，整个经济估计损失9亿至18亿美元。最后，冠状病毒能够在不同物种之间传播，导致新的疾病，这些疾病往往具有很高的致病性。自2003年以来，这种情况已经发生了两次，导致SARS和MERS冠状病毒出现在人类人口中。目前还没有针对冠状病毒的抗病毒治疗方法，畜牧业需要更有效的疫苗来抵御多种病毒株。为了开发新的方法来应对冠状病毒，特别是治疗或预防未来未知的新出现的冠状病毒，重要的是了解所有冠状病毒如何表现和与宿主细胞相互作用的共性。病毒RNA的合成是冠状病毒生命周期的一个阶段，高度保守，对新病毒颗粒的繁殖至关重要。这需要指导病毒蛋白的生产，以组成新的颗粒，并产生病毒基因组的副本，以包装成新的颗粒。冠状病毒RNA合成发生在称为复制细胞器(ROS)的专门位置。我们的发现表明，ROS的外观在所有冠状病毒中都是保守的。然而，关于ROS是如何形成的，以及需要哪些病毒和细胞蛋白，人们知之甚少。我们认为，由于它们在病毒复制中的核心作用，以及它们的外观高度保守的事实，所有冠状病毒都将劫持或使用相同的宿主蛋白核心集，以实现最佳的RO组装和功能。了解所有冠状病毒需要哪些细胞蛋白才能完成病毒复制的这一关键阶段，将为通用抗冠状病毒药物的开发、疫苗病毒的开发甚至抗药性家畜的开发奠定基础。在这个项目中，我们的目标是识别和比较存在于五种冠状病毒的ROS中的病毒和细胞蛋白，以确定冠状病毒生命周期这一关键步骤所需的核心宿主蛋白集。

Coronaviruses are an important group of pathogens that infect both humans and livestock animals. Human coronaviruses mainly cause common cold-type illnesses and are responsible for approximately 10% of hospitalizations due to respiratory infections. In addition, an estimated 34 million working days were lost as a result of coughs and colds in 2016 meaning coronaviruses contribute to a major source of lost productivity. Coronaviruses are also responsible for economically important livestock diseases. The UK poultry industry contributes £3.4 billion annually to the economy and the most economically damaging infectious disease is caused by the coronavirus infectious bronchitis virus, with an estimated £23 million lost per year due to the disease. In pigs, an outbreak of another coronavirus, porcine epidemic diarrhoea virus, in the USA in 2013-2014 is estimated to have resulted in the death of 8 million pigs and is associated with estimated losses of $900 million - $1.8 billion across the whole economy. Finally, coronaviruses are able to jump between species resulting in new diseases, which are often highly pathogenic. This has happened twice since 2003 resulting in the emergence of SARS- and MERS-coronaviruses into the human population. There are currently no antiviral treatments available for coronaviruses and livestock industries require more effective vaccines that protect against multiple strains of virus. In order to develop new approaches to tackle coronaviruses, in particular ways to treat or prevent future, as yet unknown emerging coronaviruses, it is important to understand commonalities in how all coronaviruses behave and interact with their host cells.The synthesis of viral RNA is one stage of the coronavirus life cycle that is highly conserved and is critical for the propagation of new virus particles. This is required to direct the production of viral proteins that make up new particles and to produce copies of the viral genome to be packaged into new particles. Coronavirus RNA synthesis takes place at specialized sites called replication organelles (ROs). Our findings have shown that the appearance of ROs is conserved across all coronaviruses. However, little is known about how ROs form and which viral and cellular proteins are required. We propose that due to their central role in virus replication, and the fact that their appearance is highly conserved, all coronaviruses will hijack or use the same core set of host proteins to allow optimal RO assembly and function. An understanding of which cellular proteins all coronaviruses need to complete this critical stage of virus replication will underpin the development of universal anti-coronaviral drugs, development of vaccine viruses and even resistant livestock animals. In this project, we aim to identify and compare the viral and cellular proteins that are present in the ROs of a panel of five coronaviruses to identify the core set of host proteins required for this critical step of the coronavirus life cycle.