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Every century the world will witness a major pandemic. Most active clinicians and researchers alike only have knowledge of the Spanish flu pandemic from medical history. At that time, the exact viral cause of the disease was not known, and neither was there a therapy nor a vaccine. Today, 102 years later, SARS-CoV-2 has infected millions of patients all over the world, with over 400,000 deaths at the time of writing.Pneumoniahas interviewed Frank van Kuppeveld and Berend Jan Bosch from Utrecht University, and Manish Sagar at Boston University School of Medicine, to hear their views on the cause and consequences, the present and the future of this new corona virus, SARS-CoV-2.

Now (May 2020) that we know more about the epidemiology of COVID-19, the cellular targets, and the pathophysiology of SARS-CoV-2, how does this strain compare with the other coronavirus that we have had, including the SARS and MERS coronaviruses?

BJB: Currently there are 4 circulating coronaviruses in humans. They cause common colds and (therefore) never received much attention from the medical community.

fk：该陈述的一个典型例证是，只有在SARS-COV-1爆发后发现了2种循环电晕病毒NL63和HKU1。

BJB: In the veterinary world (pigs, chickens, cows, cats) corona viruses are more serious pathogens, and therefore have been studied more extensively. An older brother of SARS-CoV-2 that emerged in China in 2003 was SARS-CoV, an example of a zoonotic virus which has jumped to humans and subsequently it spread from human to human. MERS-CoV mainly spreads among dromedaries, and occasionally crosses the species barrier to humans. However, the spread of this virus among humans is limited. Case fatality rate of SARS-CoV-1 is 10%; for MERS the reported 35% case-fatality rate is probably over-estimated, because many more people will have been infected. Theseroprevalence of MERS antibodiesin Saudi Arabia suggests that the virus is more widespread.

Current epidemiological data for SARS-CoV-2 are still relatively scarce but could point towards a case fatality rate of 1%. Another difference between SARS-CoV-1 and SARS-CoV-2 is that the former mainly spreads during the moment of active disease and only the latter can be spread by presymptomatic persons. Nosocomial spread of SARS-CoV-1 has been limited.

fk: SARS-CoV-1 and MERS mainly infect the cells in the lower respiratory tract, whereas SARS-CoV-2 (also) infects the upper respiratory tract. This characteristic contributes to the ease of spreading. SARS-CoV-2’s stronger binding to the ACE-2 receptor (although this is still debated) is another difference. There areadditional differencesin the structure of the Spike protein.

MS: As mentioned earlier, SARS-CoV-2 shares some similarities and has some significant differences with the other pathogenic coronaviruses such as SARS-CoV-1, MERS, HKU-1, OC43, NL63, and 229E. First, it should be noted that SARS-CoV-2 has achieved a “sweet spot” for a virus. Unlike SARS-CoV-1 and MERS, after establishing infection, it does not immediately make the host sick.

此外，与SARS-COV-1和MERS不同，它不会使受感染的人死亡。SARS-COV-2的病例死亡率远低于SARS-COV-1和MERS。这是病毒的理想选择，因为它提高了传输效率。与普通的冷冠状病毒（OC43，NL63、229E和HKU-1）不同，它更具致命性，因此对人类种群产生了重大影响。SARS-COV-2使用ACE2细胞受体进行细胞进入，而SARS-COV-1和NL63也使用该受体。这表明细胞的进入和可能是潮流不是这些病毒中的主要区别因素。

高度致病性的冠状病毒（SARS-COV-1，SARS-COV-2和MERS）似乎都引发了强烈且可能不当延迟的先天免疫反应，这可能与观察到的发病率和死亡率直接相关。普通的冷冠状病毒可能不会引起类似的先天免疫反应。这种差异的机械基础仍然不确定，但是在高度致病性与更多良性人冠状病毒之间，这似乎是一个主要区别。

fk: Furthermore there are major differences in the demographics of SARS-CoV-1 and SARS-CoV-2 patients. SARS-CoV-1 patients were adults >25 years of age, around 60% women, andwithout specific preference for the elderly。The reason for this is unknown.

So, what is in your view the most important mechanism that causes the severe pneumonia and the prolonged requirement for ventilatory support?

fk：这是一个主要且重要的问题，答案仍然在很大程度上未知。实际上，大多数病毒或细菌性肺炎患者平均住院7天。与SARS-COV-1和流感相比，SARS-COV-2还会引起严重的细胞因子风暴。已经提出在干扰素反应中可以发现差异：SARS-COV-1是主要1型和3型的有效诱导剂；SARS-COV-2在肺部细胞中主动复制，但几乎不会诱导干扰素。可能发挥作用的另一个因素是本地vascular leakage and angioedema。

MS: I think one of the most enlightening studies for the possible mechanism for severe pneumonia is from investigators at Washington University in St. Louis. In mouse models, they demonstrated that in mice with an early innate immune response (primarily driven by monocytes and macrophages), there is limited lung pathology and morbidity. In contrast, mice that have a delayed innate immune response have高发病率和肺部损伤。肺损伤的特征是通过活化的单核细胞和巨噬细胞浸润。有趣的是，这种现象似乎与其他呼吸道病毒（如流感）不同。

Furthermore, this difference is not driven by a major difference in virus replication. The mechanistic basis for understanding why some infected people have a delayed and robust innate immune response many days after SARS-CoV-2 infection is one of the most interesting and likely useful research avenues. It will provide an important insight about the cause of severe pneumonia.

In mice, attenuating the innate immune response after infection appears to diminish morbidity and mortality. In humans also, use of immune modulators, such as IL-6 receptor and IL-1 receptor blockers, appears to provide benefit. GR: All in all, the (immuno)pathology of COVID-19 may have the characteristics of a Macrophage Activation Syndrome.

BJB: It is disappointing that many of the potential drugs (existing and developed) for which the hopes were high, now in practice show no (such as with hydroxychloroquine) or limited effectivity. Preliminary data indicate that Remdesivir reduces the duration of intensive care treatment from 15 to 11 days,but show little effect on mortality。

Currently at least 70 companies and institutes are working on developing a vaccine. Until the moment that those vaccines will become available, do you see a role for passive vaccination (either with plasma from recovered patients or otherwise) as a form of treatment?

BJB:就像active vaccination, also passive immunization requires all 3 phases of clinical testing before it can be applied. Scaling is a major issue: administration of convalescent serum can turn out to be an effective treatment but certainly not for large groups of patients (read more这里和这里).定义的单克隆抗体against relevant epitopes could be used in selected patients, but not as preventive treatment for large populations.

MS：我看不到被动疫苗的重要作用。鉴于大量感染和易感人群，康复性血浆是一种普遍的预防和治疗是不可行的。目前，由于没有评估中和效力的标准措施，因此很难确定哪种血浆适合治疗和可能治疗。与康复等离子体相关的成本和物流使其作为群众的解决方案不可行。单克隆抗体的合成单一或鸡尾酒更可行，尽管仍然可能过于良好。

That said, understanding the impact of monoclonal antibodies and antibodies present in convalescent serum is very important. It will provide unique scientific insights for understanding antibody-based prevention and treatment. It can be used in specific cases, but it is not likely relevant as a mass treatment or prevention strategy.

The circulating coronavirus which cause mild respiratory diseases have been around for centuries. NL63 probably came from bats more then 500 years ago, OC43 may have jumped from cattle to humans in the 19^thcentury. Could you give your thoughts on how SARS-CoV-2 could evolve in the future, to begin with next winter period?

BJB：不能排除在循环冠状病毒和当前的SARS-COV-2引起的抗体之间存在一定程度的交叉反应。这是否会导致相对保护或更严重的疾病是一个现在无法回答的问题。循环冠状病毒和SARS-COV-2之间的峰值蛋白的氨基酸同源性很低。S1，尖峰蛋白的球形顶部结构域高度可变，并且在各种冠状病毒之间没有抗原交叉反应。S2是具有更保守的序列的茎。但是，即使在保守的S2区域中，迄今为止，还没有发现与α和β冠状病毒结合的抗体。

MS: SARS-CoV-2 will most probably continue to infect the human population. First, there is a large portion of the human population that remains susceptible. It is estimated based on the R₀，大约有66％的人口必须先事先感染才能获得某种形式的牛群免疫。在先前感染的患者中，我怀疑SARS-COV-2将继续感染人员。SARS-COV-2 SPIKE将继续进行较小的修改，以限制现有抗体的中和能力。然而，随着重新感染，我怀疑疾病病程比以前的疾病温和。我将这些预测基于人口中流感的进化。

The circulating coronavirus which now cause common cold like symptoms were much more severe when they first appeared between 200 and 500 years ago. What would the prospects be for SARS-CoV-2? How long would it take before it would obtain the phenotype of a common cold virus.

fk: The target population for severe COVID-19 are the elderly. Two to five centuries ago, that target population was much smaller in size, and first exposure to the virus would have taken place at a younger age. NL63, like SARS-CoV-2 also an ACE2 receptor entering coronavirus, now is a common cold virus. Accessory viral genes which may determine the interaction with the immune system could play a role.

BJB: We have to keep in mind that we are dealing with a novel virus, which made its entry into an immunological naïve population. Virgin soil epidemic is theterm coined by Alfred W. Crosbyfor this situation. Over time this will change, also with development of herd immunity and exposure at an early age, with consequence for the pattern of morbidity and mortality. At the same time, this may impact the behavior of the virus. For 229E coronavirus,mutations hotspotsare found in the spike protein domains which are essential for viral entry into the cell.

fk：病毒进化的唯一标准是扩散程度，而SARS-COV-2在这方面非常成功。

MS: I suspect that SARS-CoV-2 will continue to infect human populations because it has established a strong foothold. As already stated earlier, I think we will have seasonal infections but re-infections in previously infected hosts will lead to a milder clinical syndrome. It is hard to know if SARS-CoV-2 will have similar benign phenotype as the common coronaviruses in the next 50 years or longer.

弗兰克·范·库珀维尔教授is Professor of Molecular Virology at the Faculty of Veterinary Medicine of Utrecht University in Utrecht, The Netherlands. His research focuses on the method of replication of RNA viruses in host cells. Specifically, he studies how these viruses are able to “hijack” certain cellular factors and structures in order to replicate their RNA genome. He also researches how these viruses are able to suppress the cells’ antiviral resistance mechanisms. His current research focuses on 1) virus structure, receptors and entry mechanisms, 2) viral genome replication, 3) development of antiviral drugs, and 4) innate host responses and viral countermeasures.

Dr. Berend-Jan Boschis Associate Professor of Molecular Coronavirology Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. He studies coronaviruses: a group of viruses that may occasionally switch host species and can jump from mammals or birds to humans. Bosch is currently researching an antibody that blocks infection by the novel coronavirus SARS-CoV-2 in cells. Bosch is trying to comprehend the interaction between coronaviruses and their hosts, be they animals or humans. How do viruses infect their hosts? How do viruses avoid their hosts’ immune responses? How do viruses jump from animals to humans and cause disease? With a detailed understanding, it will become possible to develop drugs and vaccines.

Manish Sagar博士医学副教授Bosto吗n University School of Medicine. His laboratory is interested in human immunodeficiency virus type 1 (HIV-1) in particular to understand the biological mechanisms for the selection observed during HIV-1 transmission.Laboratory studies explore the hypothesis that during transmission there is selection of specific variants with properties that confer fitness for transmission. Another focus in the lab is to decipher correlates of immune protection. Dr. Sagar has served on numerous committees including NIH study sections and Doris Duke Charitable Foundation Early Career Development Award Review Committee. He is an active member of the Infectious Diseases Society of America (IDSA).