世界 【重磅】数十位科学家联名致信著名医学杂志质疑病毒起源(中英文对照全文)

【重磅】数十位科学家联名致信著名医学杂志质疑病毒起源(中英文对照全文)

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新闻简述:9月3日著名医学期刊《医学病毒学》(Journal of Medical Virology)发表了数十位来自世界各地的科学家联名致信该期刊主编的经同行评议过的信件。该文对新型冠状病毒来源于蝙蝠冠状病毒,特别是RaTG13的行业共识提出了质疑。新型冠状病毒是第七种人冠状病毒,但也是第一个且是唯一一个具备大流行潜力的人冠状病毒。然而,其宿主取向/适应模式与其它冠状病毒存在显著差异,这就引起了关于新型冠状病毒的近端起源的讨论。

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Letter to the Editor

致编者信函

Questions concerning the proximal origin of SARS-CoV-2 

关于新型冠状病毒近端起源的问题

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jmv.26478.

这篇文章已被接收出版,并通过完整的同行评审,但未经编辑、排版、分页和校对等过程,这可能会导致该版本与原版间产生差异。请将该文章引用为doi: 10.1002/ jvm .26478。

Keywords: Coronavirus, Genetic Variability, Mutation, Fusion Protein

关键词 :冠状病毒,遗传变异,突变,融合蛋白

Summary:

总结:

There is a consensus that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) originated naturally from Bat coronaviruses (CoVs), in particular RaTG13. However, the SARS-CoV-2 host tropism/adaptation pattern has significant discrepancies compared to other CoVs, raising questions concerning the proximal origin of SARS-CoV-2. The flat and non-sunken surface of the sialic acid-binding domain of SARS-CoV-2 spike protein (S protein) conflicts with the general adaptation and survival pattern observed for all other CoVs. Unlike RaTG13, SARS-CoV-2 recombination presumably occurred between the S1/S2 domains of S protein enabling host furin protease utilization. Although millions of recorded cases have been recorded globally, SARS-CoV-2 S protein does not have any apparent further recombination, placing it in conflict with the recombination models of other CoVs. Similarly, the S protein receptor-binding domain (RBD) of SARS-CoV-2 has not accumulated high-frequency non-synonymous substitutions, differentiating SARS-CoV-2 from other CoVs that have positive selection/adaptation mutations in their RBDs. 

有一个共识:严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)自然起源于蝙蝠冠状病毒(CoVs),特别是RaTG13。然而,与其它冠状病毒相比,SARS-CoV-2的宿主取向/适应模式存在显著差异,这就引发了关于SARS-CoV-2近端起源的问题。SARS-CoV-2刺突蛋白(S蛋白)的唾液酸结合结构域平坦而非凹陷的表面与所有其它冠状病毒的一般适应性和生存模式相违背。与RaTG13不同的是,SARS-CoV-2重组可能发生在S蛋白的S1/S2结构域之间,从而可以利用宿主弗林蛋白酶。尽管全球记录了数百万病例,但SARS-CoV-2 S蛋白没有出现任何明显的进一步重组,这使其与其它冠状病毒的重组模型相违背。同样,SARS-CoV-2的S蛋白受体结合域(RBD)并未积累高频率非同义替代,这将SARS-CoV-2与其他RBDs选择/适应性突变的冠状病毒区别开来。

Discussion

讨论

Andersen and colleagues documented the possible natural origin of SARS-CoV-2 from BatCoV RaTG13 1,2. SARS-CoV-2 is the seventh zoonotic CoV virus capable of infecting humans, but the first and only human coronavirus (HCoV) with pandemic potential 3. Bat or rodent CoVs demonstrate certain specific changes in the S protein receptor-binding domain (RBD), as well as the S protein glycan-binding N-terminal domain (NTD), during host tropism/adaptation 4,5. SARS-CoV-2, unlike other CoVs, does not have those signature changes, suggesting that these RBD and NTD subdomains are of very recent origin.

Andersen和他的同事记录了SARS-CoV-2可能的自然来源是蝙蝠冠状病毒 RaTG13 1,2。SARS-CoV-2是第七种能够感染人类的人畜共患冠状病毒,但也是第一个且是唯一一个具备大流行潜力的人冠状病毒(HCoV) 3。蝙蝠或啮齿类动物的冠状病毒在宿主向性/适应过程中,S蛋白受体结合域(RBD)和S蛋白多糖结合N端结合域(NTD)发生了特定的变化4,5。与其它冠状病毒不同,SARS-CoV-2没有这些特征变化,这表明这些RBD和NTD子域是最近才出现的。

The “Canyon Hypothesis” explains the development of canyons, depression zones or cavities on the surfaces of influenza virus, human rhinovirus, and Meningo viruses 6 . In CoVs (except SARS-CoV-2), the S protein NTD domain has several predicted glycanbinding domains, with a common feature being the hidden localization of these glycan binding domains to cavities to limit their access to antibodies and immune cells 5 . This pattern of CoVs is thought to be an evolutionary measure to restrict the recognition of these active sites by host immune system 4

“峡谷假说”解释了流感病毒、人类鼻病毒和脑膜炎病毒表面的峡谷、凹陷区或空腔的发展6。在冠状病毒(SARS-CoV-2除外)中,S蛋白NTD结构域有几个可预测多糖结合域,其共同特征是这些多糖结合域在腔中的隐蔽定位从而限制它们与抗体和免疫细胞接触5。这冠状病毒模式被认为是一种进化措施,以限制宿主免疫系统识别这些活性位点。

HCoVs can evade detection by host glycan-binding immune receptors. Comparative genomic analysis of six HCoVs with their corresponding native bat or rodent CoVs suggests compatibility with the “Canyon Hypothesis” resulting from various adaptive S protein NTD non-synonymous mutations near or at the glycan binding domain which are predicted to result in these NTD domains being hidden below the protein surface5 . The predicted flat, non-sunken pattern of the SARS-CoV-2 S protein NTD glycan binding domains conflicts with this evolutionary host tropism/adaptation strategy 7.

人冠状病毒可以逃避宿主聚糖结合免疫受体的检测。对六种人冠状病毒及其相应的当地蝙蝠或啮齿动物冠状病毒进行比较基因组分析表明,与多糖结合域附近的各种适应性S蛋白NTD非同义突变导致的“峡谷假说”具有相融性,预计这些突变会导致这些NTD域被隐藏在蛋白质表面之下5。预测的SARS-CoV-2 S蛋白NTD聚糖结合域的预测平坦、非凹陷模式与这种进化宿主趋向性/适应策略相违背7

A template-switching mechanism is presumably responsible for the high rate of RNA recombination in CoVs. In host cells, CoV RNAs show discontinuous RNA synthesis materialized by pauses of the RNA-dependent complex and subsequent jumps to downstream template acceptor sequences. This process results in subgenomic minus strand RNAs which serve as templates for subgenomic mRNAs. Due to the mechanistic similarity to recombination, this process might be at the origin of recombinant CoVs co-opting other CoV or even host related sequences8. Instances include the mouse hepatitis coronavirus S protein NTD sialic acid binding domain, likely arising from recombination of viral RNA with human galectin RNA sequences 8.

一种模板转换机制可能是冠状病毒(CoVs)与 RNA高重组率的原因。在宿主细胞中,冠状病毒RNA呈现出不连续的RNA合成,表现为依赖RNA的复合物间歇并随后跳转到下游模板受体序列。这一过程产生亚基因组负链RNA,作为亚基因组mRNA的模板。由于重组机制的相似性,这一过程可能是起源于重组冠状病毒(CoV)吸收其它冠状病毒(CoV)甚至宿主相关的序列8。例如,小鼠肝炎冠状病毒S蛋白NTD唾液酸结合域,可能由病毒RNA与人乳糖蛋白RNA序列重组而产生8

The furin recognition motif present at the SARS-CoV2 S1/S2 junction has no analogy in other “linage B” beta-coronaviruses, including neither pangolin-CoV nor RaTG13 1 . This indicates that the S protein S1/S2 junction is not a hot spot for RNA recombination termination that depends on a pattern swapping templates (copy-choice) 8 . Additionally, clinical isolates of SARS-CoV-2 S protein have not indicated any further recombination in this S1/S2 area, suggesting that the addition of a motif for S1/S2 site furin cleavage constituted a unique recombination occurrence. Finally, the CoV-unique insertion of 4 amino-acids creating a novel RRAR furin cleavage site introduces two arginine codons CGG-CGG, whose usage is extremely rare in CoVs, further supporting the hypothesis of a unique recombination occurrence.

在SARS-CoV2 S1/S2接合处存在的弗林蛋白酶识别基序在其他“linage B”-冠状病毒中没有类比,包括穿山甲冠状病毒和RaTG13 1。这说明S蛋白S1/S2连接并不是RNA重组终止的热点,RNA重组终止依赖于模式交换模板(copy-choice) 8。此外,临床分离到的SARS-CoV-2 S蛋白在这个S1/S2区域没有任何进一步的重组,这表明为S1/S2位点添加的基序弗林蛋白酶裂解构成了一个独特的重组。最后,4个氨基酸在冠状病毒(CoV)中独特的插入,形成了一个新的RRAR弗林蛋白酶裂解位点,引入了两个精氨酸密码子CGG-CGG,这两个精氨酸密码子在冠状病毒(CoVs)中使用极为罕见,进一步支持了发生独特重组的假设。

HCoVs have high-frequency “hot spots” for non-synonymous amino acid replacements that can possibly create positive selection for host tropism/adaptation, resistance to neutralizing antibodies, or immune evasion 2 . Interestingly, clinical SARS-CoV-2 isolates to date have only a single high frequency non-synonymous mutation, D614G, in their S protein 9. Based on currently known mutation rates and patterns in clinical isolates of SARS-CoV-2, the S protein does not appear to be a mutational “hot spot” for SARSCoV-2, unlike other human CoVs. 

人冠状病毒(HCoVs)为非同义氨基酸提供高频替换“热点”,这些替换可能会趋向宿主趋同性/适应、而对中和抗体或免疫逃避产生抵抗2。有趣的是,迄今为止临床分离的SARS-CoV-2在其S蛋白中只有一个高频非同义突变,D614G9。对临床分离株SARS-CoV-2,根据目前已知的变异率和模式, 不像其它人冠状病毒,S蛋白似乎没有SARS CoV-2突变的“热点”。

SARS-CoV-2 is the seventh HCoV, but the first HCoV with pandemic potential. SARSCoV disappeared without a pandemic, and MERS-CoV is mostly endemic to the Arabian Peninsula with some additional limited traveler infections resulting in outbreaks in South Korea 3,4. These unique features of SARS-CoV-2 raise several questions concerning the proximal origin of the virus that require further discussion. 

SARS-CoV-2是第七种人冠状病毒,却是第一个具有大流行潜力的人冠状病毒。非典在大流行前就消失了,MERS-CoV主要是阿拉伯半岛的地方传染病,另外还有部分有限的旅行者感染导致韩国爆发3,4。SARS-CoV-2的这些独特特征引发几个有关该病毒近端起源的问题,还需进一步讨论。

Author Contributions:

作者贡献

M. S. conceived the study. 

A. M. B, V. N. U, A. L., and K. L. provided critical review.

N. R., D. P., A. L. S. P. S.. V. N. U, K. L.T. M. A. edited the article, 

M. S., P. A., T. M. A. formatted the article. 

All authors M. S., D. P., P. A., T. M.A., S. S. H., A. S., R. K., K. L., D. M., M. T., A. L., P. P. C., V. N. U., S. P. S., B. D. U., N. R., A. M. B. and G. Z. K. of the consortium interpreted the results and approved the final version for submission.

M. S. 构思该研究. 

A. M. B, V. N. U, A. L., and K. L. 进行重要审稿

N. R., D. P., A. L. S. P. S.. V. N. U, K. L.T. M. A.撰写文章, 

M. S., P. A., T. M. A. 排版该文章 

所有作者(M. S., D. P., P. A., T. M.A., S. S. H., A. S., R. K., K. L., D. M., M. T., A. L., P. P. C., V. N. U., S. P. S., B. D. U., N. R., A. M. B. and G. Z. K. )联合解释该结果并同意提交最终版本。

Competing Interests statement: The authors declare no competing interests.

利益冲突声明:作者声明没有利益冲突。

References 

参考文献:

1. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2.NatMed.2020;26(4):450-452.doi:10.1038/s41591-020-0820-9; 

2. Malaiyan J, Arumugam S, Mohan K, Gomathi Radhakrishnan G. An update on the 

origin of SARS-CoV-2: Despite closest identity, bat (RaTG13) and pangolin derived 

coronaviruses varied in the critical binding site and O-linked glycan residues [published online ahead of print, 2020 Jul 7]. J Med Virol. 2020;10.1002/jmv.26261. doi:10.1002/jmv.26261 

3. Forni D, Cagliani R, Clerici M, Sironi M. Molecular Evolution of Human Coronavirus Genomes.Trends Microbiol. 2017;25(1):35-48. 

doi:10.1016/j.tim.2016.09.001 

4. Hulswit RJ, de Haan CA, Bosch BJ. Coronavirus Spike Protein and Tropism Changes. Adv Virus Res. 2016;96:29-57. doi:10.1016/bs.aivir.2016.08.004 

5. Li F. Receptor recognition mechanisms of coronaviruses: a decade of structural 

studies. J Virol. 2015;89(4):1954-1964. doi:10.1128/JVI.02615-14 

6. Rossmann MG. The canyon hypothesis. Hiding the host cell receptor attachment 

site on a viral surface from immune surveillance. J Biol Chem.1989;264(25):14587- 14590. 

7. Fantini J, Di Scala C, Chahinian H, Yahi N. Structural and molecular modelling 

studies reveal a new mechanism of action of chloroquine and hydroxychloroquine 

against SARS-CoV-2 infection. Int J Antimicrob Agents. 2020;55(5):105960. 

doi:10.1016/j.ijantimicag.2020.105960 

8. Makino S, Keck JG, Stohlman SA, Lai MM. High-frequency RNA recombination of murine coronaviruses. J Virol. 1986;57(3):729-737. doi:10.1128/JVI.57.3.729-737.1986 

9. Brufsky A. Distinct viral clades of SARS-CoV-2: Implications for modeling of viral spread [published online ahead of print, 2020 Apr 20]. J Med Virol. 

2020;10.1002/jmv.25902. doi:10.1002/jmv.25902

翻译:【重生】【一花一世界】 校對:【重生】【一花一世界】编辑:【Michelle】

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joop12345
1 月 之前

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maliya
1 月 之前

谢谢整理

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123456l
1 月 之前

ccp must go to hell

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Athenahope
1 月 之前

科学界终于响应了,爆料革命和路德社开出了揭露ccp病毒的第一枪。世界正义力量,请加油!

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灭共52165 新中国联邦

take down ccp

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