每个世纪，世界都会见证一个主要的大流行。大多数活跃的临床医生和研究人员都只能从病史中了解西班牙流感大流行。当时，该疾病的确切病毒原因尚不清楚，也没有治疗和疫苗。102年后的今天，SARS-COV-2感染了世界各地数百万患者，在写作时死亡超过40万人。肺炎has 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.
现在（2020年5月），我们对Covid-19的流行病学，细胞靶标和SARS-COV-2的病理生理学有了更多的了解，这种菌株与我们所拥有的其他冠状病毒相比如何，包括SARS和MERS冠状病毒？
BJB：目前，人类有4个循环冠状病毒。它们会引起普通感冒，因此（因此）从未受到医学界的关注。
fk: A typical illustration for this statement is that 2 of the circulating corona viruses, NL63 and HKU1, were only identified after the outbreak of SARS-CoV-1.
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. TheMERS抗体的血清阳性在沙特阿拉伯，该病毒更为广泛。
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 are其他差异在尖峰蛋白的结构中。
多发性硬化症：如前所述，SARS-COV-2具有一些相似之处，并且与其他致病性冠状病毒（例如SARS-COV-1，MERS，HKU-1，OC43，NL63和229E）有显着差异。首先，应该指出的是，SARS-COV-2为病毒获得了“最佳位置”。与SARS-COV-1和MERS不同，在建立感染后，它并没有立即使宿主生病。
Furthermore, unlike SARS-CoV-1 and MERS, it does not make the infected person deathly ill. The case fatality rate for SARS-CoV-2 is much lower than SARS-CoV-1 and MERS. This is ideal for the virus because it increases transmission efficiency. Unlike the common cold coronaviruses (OC43, NL63, 229E, and HKU-1), it is more lethal and thus has had and will have a major impact on human populations. SARS-CoV-2 uses the ACE2 cellular receptor for cell entry, and SARS-CoV-1 and NL63 also use this receptor. This suggests that cellular entry and presumably tropism is not the primary distinguishing factor among these viruses.
The highly pathogenic coronaviruses (SARS-CoV-1, SARS-CoV-2 and MERS) all appear to initiate an intense and possibly inappropriately delayed innate immune response, which may be directly correlated to the observed morbidity and mortality. The common cold coronaviruses may not induce a similar innate immune response. The mechanistic basis for this discrepancy remains uncertain, but it appears to be a major difference among the highly pathogenic versus more benign human coronaviruses.
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。原因是未知的。
那么，在您看来，最重要的机制是什么导致严重的肺炎和对通气支撑的延长需求？
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hardly induces interferons。Another factor which may play a role is local血管泄漏和血管性水肿。
多发性硬化症：我认为，严重肺炎可能机制的最具启发性研究之一是圣路易斯华盛顿大学的研究人员。在小鼠模型中，他们证明在早期先天免疫反应（主要由单核细胞和巨噬细胞驱动）的小鼠中，肺病理和发病率有限。相反，先天免疫反应延迟的小鼠已经high morbidity and lung damage。肺损伤的特点是渗透by activated monocytes and macrophages in the lung. Interestingly, this phenomenon appears to be different from other respiratory viruses, such as influenza.
此外，这种差异不是由病毒复制的主要差异驱动的。理解为什么某些受感染者在SARS-COV-2感染后数天内有延迟和强大的先天免疫反应的机理基础是最有趣，可能有用的研究途径之一。它将提供有关严重肺炎原因的重要见解。
在小鼠中，感染后的先天免疫反应减少了发病率和死亡率。在人类中，使用免疫调节剂（例如IL-6受体和IL-1受体阻滞剂）的使用似乎提供了益处。GR：总的来说，Covid-19的（免疫）病理可能具有巨噬细胞激活综合征的特征。
BJB：令人失望的是，许多潜在的药物（现有和开发）是希望很高的，现在实际上显示了NO（例如羟氯喹）或有限的效果。初步数据表明，Remdesivir将重症监护治疗的持续时间从15天减少到11天，但是对死亡率几乎没有影响。
目前至少有70家公司和机构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：像主动疫苗接种一样，被动免疫也需要进行所有3个临床测试的阶段。缩放是一个主要问题：疗养血清的给药可能是一种有效的治疗方法，但对于大量患者来说肯定不是（阅读更多）这里and这里）。Defined monoclonal antibodiesagainst relevant epitopes could be used in selected patients, but not as preventive treatment for large populations.
多发性硬化症: I don’t see a massive role for passive vaccination. Given the massive number of infected and susceptible people, convalescent plasma as a generalized prophylaxis and treatment is not feasible. At this time, it is difficult to determine which plasma is appropriate for therapy and possibly treatment because there are no standardized measures for assessing neutralization potency. The costs and logistics associated with convalescent plasma make it unfeasible as a solution for the masses. Synthetic single, or a cocktail of, monoclonal antibodies are more feasible although still likely cost-prohibitive.
就是说，了解康复血清中存在的单克隆抗体和抗体的影响非常重要。它将为理解基于抗体的预防和治疗提供独特的科学见解。它可以在特定情况下使用，但不可能与大规模治疗或预防策略相关。
引起轻度呼吸系统疾病的循环冠状病毒已经存在了几个世纪。NL63可能来自500年前的蝙蝠，OC43可能在19号中从牛跳到人类th世纪。您能想到SARS-COV-2将来如何从下一个冬季开始的想法吗？
BJB: It cannot be excluded that there is a certain degree of cross-reactivity between antibodies induced by circulating coronaviruses and the current SARS-CoV-2. Whether this would lead to relative protection or to a more serious disease is a question that can not be answered right now. Aminoacid homology of Spike proteins between circulating coronaviruses and SARS-CoV-2 is low. S1, the globular top domain of the Spike protein is highly variable and shows no antigenic cross-reactivity between the various coronaviruses; S2 is the stalk with a more conserved sequence. But even among the conserved S2 regions, thus far no antibodies have been found that bind to both alpha and beta coronaviruses.
多发性硬化症：SARS-COV-2很可能会继续感染人口。首先，有很大一部分人口仍然容易受到影响。它是根据r估算的0，，，，that around 66% of the human population would have to prior infection to obtain some form of herd immunity. Among the previously infected patients, I suspect that SARS-CoV-2 will continue to infect people. The SARS-CoV-2 spike will continue undergoing minor modifications that limit the neutralization capacity of pre-existing antibodies. With re-infection, however, I suspect that the disease course will be milder than previous disease. I base these predictions on evolution of influenza within human population.
现在，循环冠状病毒在200到500年前首次出现时，如今引起普通感染症状的情况要严重得多。SARS-COV-2的前景将是什么？它需要多长时间才能获得普通冷病毒的表型。
fk：严重的Covid-19的目标人群是老年人。两个到五个世纪前，该目标人群的大小要小得多，首先接触该病毒会在年轻时发生。NL63就像SARS-COV-2一样，也是进入冠状病毒的ACE2受体，现在是一种常见的冷病毒。可以确定与免疫系统相互作用的辅助病毒基因可以起作用。
BJB：我们必须记住，我们正在处理一种新型病毒，这使其进入免疫学幼稚。维珍土壤流行是由阿尔弗雷德·克罗斯比（Alfred W. Crosby）创造的术语对于这种情况。随着时间的流逝，这也会随着畜群免疫和暴露于早年的发展而改变，并导致发病率和死亡的模式。同时，这可能会影响病毒的行为。对于229e冠状病毒，突变热点are found in the spike protein domains which are essential for viral entry into the cell.
fk: The only criterion for viral evolution is the degree of spreading, and SARS-CoV-2 has been extremely successful in that respect.
多发性硬化症: 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·库珀维尔教授是荷兰乌特雷希特大学兽医学院的分子病毒学教授。他的研究重点是宿主细胞中RNA病毒复制的方法。具体而言，他研究了这些病毒如何能够“劫持”某些细胞因子和结构以复制其RNA基因组。他还研究了这些病毒如何能够抑制细胞的抗病毒抗性机制。他目前的研究重点是1）病毒结构，受体和进入机制，2）病毒基因组复制，3）抗病毒药的开发以及4）先天宿主的反应和病毒对策。
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博士是波士顿大学医学院的医学副教授。他的实验室对人类免疫缺陷病毒1型（HIV-1）尤其是为了了解在HIV-1传播过程中观察到的选择的生物学机制。实验室研究探讨了以下假设：在传播过程中，在传播过程中选择具有赋予特定变体的特定性能，这些属性赋予适合传输。实验室的另一个重点是破译免疫保护的相关性。Sagar博士曾在NIH研究部分和多丽丝·杜克慈善基金会早期职业发展奖审查委员会等众多委员会任职。他是美国传染病学会（IDSA）的积极成员。
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