Structural studies of viruses and their interactions with cells

过去，病毒性疾病是造成大规模流行病的主要原因，最著名的例子是1918年的流感暴发。近年来，我们幸运地躲过了这样的全球灾难，但仍然存在着真实和现实的风险。因此，世卫组织全球防备监测委员会(https://apps.who.int/gpmb/assets/annual_report/GPMB_annualreport_2019.pdf)在2019年9月的报告中警告说，“存在着一种快速传播的、高度致命的呼吸道病原体大流行的非常真实的威胁，导致5000至8000万人死亡，并抹去世界经济的近5%”。他们需要采取的行动之一是“确保在创新疫苗和疗法的开发、激增的制造能力、广谱抗病毒药物和适当的非药物干预方面进行足够的投资”。这里提出的方案并不主要针对致命性呼吸道病毒，但它确实针对两个重要的病毒病原体家族，即微冠状病毒科和呼肠孤病毒科。微小核糖核酸病毒不仅造成很大比例的呼吸道感染，而且还造成其他主要流行病，特别是每年数百万例手足口病病例。虽然最著名的小核糖核酸病毒病之一脊髓灰质炎几乎被消灭，但最近(https://www.who.int/news-room/detail/07-01-2020-statement-o-the-twenty-third-ihr-emergency-committee-regarding-the-international-spread-of-poliovirus)病例有令人担忧的增加，另一种肠道病毒仍有严重的急性迟缓性麻痹病例。两个共感染的小核糖核酸病毒之间频繁发生重组事件，无疑会导致大量小核糖核酸病毒引起的疾病的出现和重新出现。同样，在呼肠孤病毒科中，轮状病毒估计每年导致数亿例胃肠炎。因此，我们建议针对的病毒代表着重大的全球健康负担，但仍然有相当少量的疫苗可用，也没有获得许可的抗小核糖核酸病毒药物。显然，对新疗法的需求尚未得到满足。由于冷冻电子成像的持续革命，现在是结构病毒学的黄金时代，但我们对它们如何工作的理解仍然存在重大差距。推动当前计划的想法是，综合结构生物学现在已经足够强大，它可以提供丰富的原子水平信息，用于寻找新的治疗方法，但也可以有助于更广泛的细胞层面对病毒生命周期的全部复杂性的理解。该方案的目标是为回答一些基本问题作出真正的贡献，并至少确定改善治疗的方向。

Viral diseases have been responsible for massively damaging pandemics in the past, the best known example being the influenza outbreak of 1918. In recent years we have mercifully escaped such global disasters, however there is still a real and present risk. Thus the September 2019 report of the WHO Global Preparedness Monitoring Board (https://apps.who.int/gpmb/assets/annual_report/GPMB_annualreport_2019.pdf) warned that "there is a very real threat of a rapidly moving, highly lethal pandemic of a respiratory pathogen killing 50 to 80 million people and wiping out nearly 5% of the world's economy". One of their required actions is "ensure adequate investment in development of innovative vaccine and therapeutics, surge manufacturing capacity, broad-spectrum antivirals and appropriate non-pharmaceutical interventions". The programme proposed here does not primarily address lethal respiratory viruses, however it does address two important families of viral pathogens, the Picornaviridae and the Reoviridae. Picornaviruses are responsible not only for a very large proportion of respiratory tract infections, but also for other major epidemics, notably several million cases per year of hand-foot-and-mouth disease. Although one of the best known picornavirus diseases, polio, is almost eliminated there has been a concerning increase in cases recently (https://www.who.int/news-room/detail/07-01-2020-statement-o-the-twenty-third-ihr-emergency-committee-regarding-the-international-spread-of-poliovirus) and there are still serious cases of acute flaccid paralysis due to another enteroviruses. Frequent recombination events occurring between two co-infecting picornaviruses will no doubt lead to the emergence and re-emergence of numerous picornavirus caused diseases. Similarly, amongst the Reoviridae rotaviruses are estimated to cause several hundred million cases of gastroenteritis every year. Thus the viruses we propose to target represent significant global health burdens, but there are still a rather small number of vaccines available and no licenced anti-picornavirus drugs. There is a clear unmet need for novel therapeutics. Due to the continuing revolution in cryo-electron imaging it is now a golden age for structural virology and yet there remain major gaps in our understanding of how they work. The idea driving the current programme is that integrated structural biology is now sufficiently powerful that it can provide a wealth of atomic level information to feed into the search for new therapies, but can also contribute to the broader cellular level understanding of the full complexity of the virus life cycle. The goal of this programme is to make genuine contributions to answering some fundamental questions, and to at least set a direction of travel towards improved treatment.